Pediatric Obesity: Pharmacokinetics and Implications for Drug Dosing

Clinical Therapeutics/Volume 37, Number 9, 2015

Review Article

Pediatric Obesity: Pharmacokinetics and Implications for Drug Dosing Jennifer G. Kendrick, BSc(Pharm), PharmD1; Roxane R. Carr, BSc(Pharm), PharmD, BCPS, FCSHP1,2; and Mary H.H. Ensom, BS(Pharm), PharmD, FASHP, FCCP, FCSHP, FCAHS1,2 1

Pharmacy Department, Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia, Canada; and 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT Purpose: Clinicians are increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess weight likely leads to alterations in pharmacokinetics. The purpose of this article was to describe the pharmacokinetics and pharmacodynamics in overweight and obese children and, where possible, provide recommendations for drug dosing. Methods: EMBASE (1980–May 2015), MEDLINE (1950–May 2015), and International Pharmaceutical Abstracts (1970–May 2015) databases were searched by using the following terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles. References of relevant articles were searched to identify additional studies. Findings: Total body weight (TBW) is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; providing standard adult doses may be insufficient, however. Obese children may also require less vancomycin and aminoglycosides

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September 2015

per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) is warranted. Obese children require less propofol than normal-weight children; however, there is limited information about the dosing of other anesthetics or opioids. Implications: Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some of the studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, our understanding of the pharmacokinetics in obese children is still limited. When dosing information is not available for obese children, it may be necessary to extrapolate from available data in obese adults, but one should consider the effects of the child’s age on pharmacokinetics. (Clin Ther. 2015;37:1897–1923) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: drug dosing, obesity, pediatric, pharmacodynamic, pharmacokinetic.

Accepted for publication May 19, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.05.495 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics

INTRODUCTION

Definitions

In 2013, the World Health Organization (WHO) estimated that 42 million children aged o5 years were overweight, with 75% of those children living in developing countries.1 Worldwide, the prevalence of overweight and obese children increased from 4.2% in 1990 to 6.7% in 2010.2 In a 2009 to 2010 survey, 12% of children aged 2 to 5 years and 18% of children aged 6 to 19 years in the United States were obese, defined as a body mass index (BMI) Z95th percentile.3 Compared with normal-weight children, overweight or obese children are at higher risk of chronic diseases, including type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovary syndrome, asthma, obstructive sleep apnea, pseudotumor cerebri, gastroesophageal reflux disease, cholecystitis, and orthopedic problems.4–8 An association between childhood obesity and coronary artery disease in adulthood also exists.9 Obese children are also more likely to have early-onset puberty.10,11 Clinicians are therefore increasingly likely to have under their care obese children with diseases requiring pharmacotherapy. Optimal drug dosing for this population is unclear. Excess body weight likely leads to alterations in pharmacokinetics, and overweight and obese children may be at higher risk of toxicity or reduced therapeutic effectiveness. Although there are a number recent reviews describing drug dosing and pharmacokinetics in obese adults,12–18 fewer studies include children.19,20 The present article reviews pharmacokinetics and pharmacodynamics in overweight and obese children and provides recommendations for drug dosing.

Definition of “overweight” or “obese” for children is not standardized. Current WHO recommendations, using BMI for age and sex z scores Z1 SD for overweight (approximately equivalent to the 85th percentile) and Z2 SDs for obese (approximately equivalent to the 97th percentile) in children aged 5 to 19 years, have been updated from their previous recommendation of using weight-for-length.1,21 The International Obesity Taskforce and the American Academy of Pediatrics recommend using BMI-forage and sex Z85th percentile and 95th percentile to define overweight and obesity, respectively, in children aged 42 years.21,22 In children aged r2 years, the term obesity is generally not applied.22 In the United States, the Centers for Disease Control and Prevention’s weight, length, and BMI reference charts, which derived data from the National Health and Examination Surveys, are widely used.21 The WHO revised their growth charts in 2006 based on data from numerous countries in their Multicentre Growth Reference Study.23 Many countries, including Canada, recommend using the WHO growth charts. Of note, the accuracy of BMI as an indicator for body “fatness” in children is variable. In children with a BMI Z95th percentile, it is a good indicator of body “fatness”; however, in children with a lower BMI, differences may more likely be due to differences in fat-free mass.24

MATERIALS AND METHODS Search Strategy We searched EMBASE (1980–May 2015), MEDLINE (1950–May 2015), and International Pharmaceutical Abstracts (1970–May 2015) databases by using the following search terms: obesity, morbid obesity, overweight, pharmacokinetics, pharmacodynamics, drug, dose, drug levels, pediatric, and child. The search was limited to English-language articles, and the references of relevant articles were also searched to identify additional studies. Studies and case reports that described pharmacokinetics, pharmacodynamics, or drug dosing in obese children were included.

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Body Composition Body composition affects disposition of drugs in obese individuals but is difficult to estimate with indirect measures, such as BMI and other size descriptors. Wells et al25 compared body composition in overweight and obese children with that of age- and sex-matched control subjects. Obese children (n ¼ 38) were on average 3.9 cm taller and had significantly higher total body water, body volume, lean mass, fat mass, and bone mineral content than normal-weight children; these values remained significant after adjusting for age, sex, and height. Information for overweight children was not reported. Fat mass was responsible for 30% to 50% of total weight and 73% of the excess weight in obese children. Lean mass was more hydrated in obese children compared with normal-weight children in this study as well as a report by Battistini et al,26 and this finding was attributed to increased extracellular water.

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J.G. Kendrick et al.

Dosing Weight Methods for dosing medication in children include: age-based dosing, allometric scaling, body surface area (BSA)-based dosing, and weight-based dosing.27 Weight-based dosing is used most commonly in clinical practice, followed by BSA-based dosing used primarily for calculating chemotherapy. BSA is most commonly calculated by using the Mosteller28 equation: BSA ¼ {[height (cm)  weight (kg)]/3600}1/2. Weight and size descriptors used in pharmacokinetic studies include TBW, ideal body weight (IBW), and adjusted body weight (ABW). IBW is derived from Metropolitan Life Insurance Tables or from the Devine or Robinson estimation in adults.29,30 In children, 3 methods have been described for estimating IBW. The McLaren method uses the 50th percentile of weight for height, and the Moore method uses the corresponding weight percentile for height.31 The BMI method uses BMI 50th percentile for age  [height (m)]. In adults, an adjusted body weight, using a cofactor of 0.4, is recommended for dosing aminoglycosides: ABW ¼ IBW þ 0.4(TBW – IBW).12 ABW using alternate cofactors has also been described. To our knowledge, ABW has not been validated in children; however, Koshida et al32 used ABW to estimate tobramycin volume at steady state (Vss). Green and Duffull29 reviewed available size descriptors used in adult pharmacokinetic studies: BMI, BSA, IBW, fat-free mass, lean body weight, ABW, TBW, and predicted normal weight. They reviewed 30 drugs, including antineoplastic agents, antibiotics, antiepileptic agents, low-molecular-weight heparins, and opioids. The authors determined that the best size descriptor for calculating Vd was TBW and that the best size descriptor for calculating clearance (CL) was lean body weight. Similar information in children was not available. It is important to consider the pharmacokinetics and available dosing information for the given drug when calculating drug doses for obese children. For some drugs, using TBW to calculate weight-based doses could provide a supratherapeutic dose and using IBW could provide a subtherapeutic dose. Regardless of the method used, it is important to consider the recommended adult maximum doses and, in some cases, what is known about dosing in obese adults.12–18

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Pharmacokinetics and Drug Dosing Differences in Obese Children Analgesic Agents No studies describing pharmacokinetic parameters of opiate agonists in obese children were found. Commonly used opiate agonists include morphine, hydromorphone, and fentanyl. Codeine is no longer commonly prescribed in children. Opiate agonists are primarily metabolized in the liver and eliminated intact or as metabolites in urine.33 Fentanyl is the most lipophilic of these opiate agonists. Burke et al34 performed a retrospective cohort study of 10,498 obese and normal-weight children who received anesthesia for noncardiac surgery (Table I). They recommended dosing for anesthetic medications, including morphine (recommended dosing based on IBW), on the basis of the limited data available for children and on pharmacokinetic data extrapolated from adult information. Obese children compared with normal-weight children were more likely to receive overdoses of morphine. Limitations of this study include that clinical outcomes were not reported and no multivariate analysis or correction for multiple comparisons occurred. Friedrichsdorf et al35 published a case report of 3 obese children who died after codeine administration at usual or lower than recommended doses (Table I). No anatomic causes of death were found, and accidental overdose was ruled out by examining medication bottles. The authors noted that codeine concentrations were potentially toxic in these patients. No information about obstructive sleep apnea was provided. Obese children should receive codeine cautiously, if at all. Ross et al36 used a decision support tool to develop dosing recommendations for commonly prescribed medications in critically ill obese children (Table I). Their tool included a usefulness scoring of the pediatric and adult literature, pharmacokinetic parameters of the drug, drug properties (lipophilic vs hydrophilic), and potential consequences of overdosing versus underdosing. They recommended dosing hydromorphone and fentanyl by using ABW (cofactor of 0.25) and morphine by using IBW and titrating to effect, which was based on adult literature. Currently, it is unknown what the best size descriptor is for dosing opiate agonists in obese children. Given that these agents have a narrow therapeutic index and that obese children may be more at risk of respiratory

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Study and Design

Drug(s)

Analgesics and anesthetics Burke et al,34 Midazolam retrospective Morphine cohort study Succinylcholine

    

Friedrichsdorf et al,35 case report



Neostigmine Cisatracurium

Codeine

Patients

  

 



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Olutoye et al,41 prospective observerblinded observational study



Propofol

 

10,498 obese (BMI 485th %) and normal weight (BMI r85th %) children

Methods



Aged 2–17 y, anesthesia for noncardiac surgery Excluded intubated postoperatively, renal or hepatic disease, neurologic impairment, sleep-disordered breathing

Case 1: 10-year-old female; weight, 44.5 kg; BMI, 24.4 kg/m2; multiple comorbidities Case 2: 6-year-old female; weight, 44.9 kg; BMI, 26.6 kg/m2; previously healthy, upper respiratory tract infection

   

Case 3: 4-year-old female; weight, 59 kg; BMI, 49.6 kg/m2; multiple comorbidities

40 obese (BMI 4 95th %) and 40 normal-weight (BMI 25th– 84th %) children



Aged 3–17 y, previously healthy, propofol anesthesia



Classified medications into dosing groups and recommended doses: midazolam and morphine based on IBW (BMI at 50% for age and sex); succinylcholine and neostigmine based on TBW; and cisatracurium based on LBW calculation used in adults (3.8  [0.0215  TBW0.65  height0.72])40 Underdose defined as 410% below recommended and overdose defined as 410% above recommended

Case1:codeine20–40mg(0.45–0.9mg/kg TBW) in afternoon and at bedtime postoperatively; also received diazepam 2 to 4 mg at bedtime Case 2: codeine 10–20 mg (0.22–0.44 mg/kg TBW) at 7 am, 3 pm, and 7 pm in combination with guaifenesin Case 3: codeine 17 mg (0.3 mg/kg TBW) at 8 am, 12 pm, 4 pm, and 8 pm post-tonsillectomy

Propofol dose based on biased coin approach: first child received 1 mg/kg IV. If desired effect not observed, next child received next higher dose in 0.25mg/kg increments. If desired effect observed, next child randomized 0.95 to 0.05 to receive same dose or next lower dose

Results

     

 

Obese children less likely to receive recommended doses than normalweight children (OR, 0.69 [95% CI, 0.64–0.75])

Conclusions



Obese children more likely than normal-weight children to receive an overdose of morphine (OR, 3.5 [95% CI, 2.7–4.4])

Obese children are less likely than normal-weight children to receive literature-recommended doses of medications used in anesthesia

Obese children more likely than normal-weight children to receive underdose of succinylcholine (OR, 2 [95% CI, 1.2–3]) Case 1: found unresponsive at 1:30 am; codeine and morphine concentrations 0.78 and 0.15 mg/L



Obese children may be at risk of codeine toxicity

Case 2: appeared blue at 7:45 pm and then unresponsive at 8 am; codeine and morphine concentrations 0.17 and 0.08 mg/L Case 3: found unresponsive in the morning; CYP2D6 analysis showed extensive metabolizer (normal phenotype) of codeine; codeine and morphine concentrations 0.69 and 0.39 mg/L Median ED95 lower in obese vs normal-weight children (2 mg/kg [95% CI, 1.8–2.2] vs 3.2 mg/kg [95% CI, 2.7–3.2]) No significant difference in % of patients with Z10 mm Hg drop in blood pressure at 2 minutes



Obese children require lower propofol doses per kilogram TBW than normal-weight children to achieve the same effect

ED95 ¼ loss of lash reflex at 20 seconds in 95% of patients

(continued)

Clinical Therapeutics

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Table I. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of analgesics, anesthetics, and neuromuscular blockers.

September 2015

Table I. (continued). Study and Design Diepstraten et al,42 prospective PK study

Drug(s)



Propofol

Patients

 

20 morbidly obese children (BMI Z30 kg/m2)

Methods



Aged 5–18 y, anesthesia with propofol for bariatric surgery

 

Ross et al,36 literature review and dosing recommendation algorithm



113 commonly prescribed medications in pediatric intensive care units in the United States

Neuromuscular blockers Rose et al,81 Succinylcholine RCT





 



122 citations for 66 medications in obese children or adults

30 obese (BMI 430 kg/m2) children Aged 9–15 y; succinylcholine for neuromuscular blockade; preoperative midazolam, ranitidine, and metoclopramide; induction with thiopental, fentanyl Reference population: 40 normal-weight children from a previous study82

 







Propofol 1000 μg/kg/min, followed by 250–350 μg/kg/min titrated by 25–50 μg/kg/min to target anesthesia depth, and blood pressure and heart rate within 30% of baseline

Results

  

Conclusions



Mean propofol CL, 161 L/h TBW was best size descriptor for CL No covariate predicted Vd

or

size

descriptor

Authors suggested propofol dosage should be based on TBW using an allometric function

Dose calculated based on ABW ¼ IBW þ (0.4  [TBW – IBW]) Blood samples at baseline and 5, 10, 15, 30, 45, and 120 minutes after start of propofol infusion Nonlinear mixed-effects modeling Decision support tool based on usefulness scoring of literature (score ¼ 1–15), medication PK properties, consequences of overdosing/ underdosing, and medication properties (hydrophilic vs lipophilic)

First 20 children were randomized to receive succinylcholine 100 μg/kg or 250 μg/kg TBW and remaining 10 children received succinylcholine 150 μg/kg TBW Neuromuscular blockade monitored with the adductor pollicis muscle response to supramaximal train-of-four stimuli of ulnar nerve every 10 seconds for 30 seconds total

    

32 medications had information in obesity

no

dosing



98 medications had no dosing information in obese children

Dosing recommendations for medications using ABW (38%), IBW (16%), and TBW (46%)

Median usefulness score of 7 (range, 0–12.6)

ED50, ED90, and ED95 in μg/kg of TBW were 152.8 (95% CI, 77.8– 299.5), 275.4 (95% CI, 142–545.7), and 344.3 (95% CI, 175.3–675.3) Similar to reference population mean (SD) ED50 and ED90: 147 (32) and 270 (70) μg/kg TBW



Succinylcholine dose per kilogram TBW provide similar response in obese and normal-weight children

Linear regression used to determine effective dose to depress 50%, 90%, and 95% of baseline muscle twitch (ED50, ED90, and ED95)

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J.G. Kendrick et al.

ABW ¼ adjusted body weight; BMI ¼ body mass index; CL ¼ clearance; CYP ¼ cytochrome P450; ED ¼ effective dose; IBW ¼ ideal body weight; LBW ¼ lean body weight; OR ¼ odds ratio; PK ¼ pharmacokinetic; RCT ¼ randomized controlled trial; TBW ¼ total body weight.

Clinical Therapeutics adverse events, it seems reasonable to exercise caution with empiric doses and to titrate to effect. Based on extrapolation from adult data, Mortensen et al37 recommend dosing fentanyl based on TBW for induction and lean body weight for maintenance of anesthesia, and Ross et al36 recommend dosing based on ABW (cofactor of 0.25) because it is a lipophilic opioid. Both Mortensen et al and Ross et al recommend dosing morphine based on IBW because it is a hydrophilic opioid.

Anesthetic Agents Although we found no pharmacokinetic studies of anesthetic agents in obese children, there are a few studies that describe dosing. There are also a number of review articles that describe the potential morbidity associated with anesthesia in obese children.37–40 In the study by Burke et al34 (Table I), obese children were less likely to receive recommended anesthetic medication doses than normal-weight children (odds ratio [OR], 0.69 [95% CI, 0.64–0.75]). However, when the medications were analyzed separately, there was no difference for midazolam (recommended based on IBW). Olutoye et al41 found in their prospective study that obese children required lower propofol doses compared with normal-weight children (Table I). The authors used loss of lash reflex as their marker of effectiveness but noted that the optimal measure of propofol effectiveness has not been determined. Diepstraten et al42 performed pharmacokinetic analyses on 20 morbidly obese children and found that TBW was the best size descriptor for CL. Based on this limited information, the authors suggested that the propofol dosage be based on TBW by using an allometric function. From these studies, it is unclear what the best size descriptor is for dosing propofol. TBW may be appropriate for the initial induction dosing of propofol, as recommended by Ross et al36 until a better size descriptor becomes available; however, obese children likely require less propofol to maintain the desired level of anesthesia compared with normal-weight children. Additional caution should be exercised when using propofol for procedural sedation in obese children.

Antibacterial Agents Penicillins Amoxicillin is a hydrophilic antibiotic that is well absorbed orally, distributes widely, and is eliminated

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primarily unchanged in urine.33 We found no studies examining the pharmacokinetics of amoxicillin or other penicillins in obese children. Christian-Kopp et al43 conducted a retrospective cohort study to examine the dosing of amoxicillin for otitis media (Table II). The authors found that heavier children received lower amoxicillin doses per kilogram TBW, likely due to the prescriber capping the dose at a usual or maximum adult dose; however, the practice of capping the dose at the usual adult maximum did not seem to differ whether prescribing for obese children or for normal-weight children. There was no difference in treatment failure or relapse in the 4 weeks after amoxicillin prescription. Given that the guidelines for otitis media recommend high-dose amoxicillin and that it has a wide margin of safety, prescribing based on TBW in obese children up to a maximum adult dose seems reasonable.44 Ross et al36 provide dosing weight recommendations for ampicillin and piperacillin/tazobactam. Their recommendations (ie, to dose both medications according to TBW by using adult maximum doses) are extrapolated from adult studies and take into consideration the wide therapeutic range and the potential for risk of underdosing. Cephalosporins Cefazolin is a water-soluble antibiotic that is widely distributed and 90% eliminated unchanged in urine.33 Koshida et al32 found that cefazolin pharmacokinetic parameters in 5 obese children were similar to those of 6 normal-weight children from a previous study45 (Table II). This small study suggests that dosing should be calculated based on TBW (Table III). Ross et al36 provide dosing recommendations for critically ill obese children receiving cephalosporins. They suggest dosing cefazolin, cefepime, cefotaxime, ceftazidime, and ceftriaxone by using TBW and adult maximum doses, which are based on risk/benefit assessments. Aminoglycosides Aminoglycoside antibiotics are water soluble, distribute primarily into extracellular fluid, and are eliminated mainly by glomerular filtration.33 Koshida et al32 found that tobramycin CL and t½ were similar in 5 obese children compared with 6 normal-weight children from a previous study45; however, Vss per TBW was significantly lower for the obese children (Table II). The authors developed an

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September 2015

Table II. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antibacterial and antiviral agents. Study and Design Antibacterials ChristianKopp et al,43 retrospective cohort study

Drug(s)



Amoxicillin

Patients

  

Methods

359 children



Aged 0–18 y (mean, 3.2 y), amoxicillin for otitis media



85 children Z20 kg; 29 children obese (weight 497th % for age)

Results

Compared dosing between obese and normal-weight children Z20 kg Compared dosing between different weight categories

  

Koshida et al,32 prospective PK study

 

Cefazolin Tobramycin

   

5 obese children Aged 22 mo–9.4 y (mean, 6.8 y), normal kidney and liver function Children 30%–78% above IBW (mean, 63%) Reference population: 6 normal-weight children from previous study54

    

Choi et al,46 retrospective cohort study



Gentamicin





25 obese (BMI Z95th %) and 25 normal-weight (BMI, 5th–85th %) children matched for age, sex, and indication for gentamicin

 



Tobramycin 2 mg/kg IV over 30 minutes Cefazolin serum concentrations at 30, 50, 70, 90, 110, 130, 160, 190, 220, and 280 minutes after start of infusion Tobramycin serum concentrations at 10, 30, 50, 70, 90, 120, 150, 180, and 240 minutes after start of infusion Noncompartmental analysis; calculated by using the trapezoidal rule

 

AUC

Cpk and Ctr used to calculate PK parameters by using the SawchukZaske method



Cpk extrapolated to end of 30 minutes’ infusion



Doses and PK parameters compared between obese and normal-weight children

 



Obese children received similar milligram per kilogram TBW doses of amoxicillin

Mean (SD) amoxicillin dose higher for children o20 kg vs Z20 kg: (74.2 [14.7] vs 40.4 [16.6] mg/kg/d; P ¼ 0.0) 8 children exceeded standard adult dose of 1500 mg/d; maximum dose 2400 mg/d No significant difference between obese versus normal-weight reference for cefazolin Vss per kilogram TBW, CL per kilogram TBW, or t½

 

Tobramycin CL per kilogram TBW and t½ similar between obese and normalweight children

Cefazolin pharmacokinetics were not altered in obese children Tobramycin Vd was lower in obese children, but other PK parameters were not altered

Mean (SD) tobramycin Vss per TBW lower for obese vs normal-weight children (0.20 [0.03] vs 0.26 [0.04] L/kg; Po 0.05)

Mean (SD) gentamicin doses given every 8 hours were lower in obese vs normal-weight children (1.86 [0.43] vs 2.25 [0.4] mg/kg; P o 0.01) Mean (SD) Cpk extrapolated higher in obese vs normal-weight children (8.17 [2.02] vs 7.06 [1.52] mg/L; P o 0.05)



Although CL was not able to be measured, similarity in ke and t½ in context of lower Vd suggest that CL per kilogram TBW may be lower in obese children

ke and t½ similar between obese and normal-weight children

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Mean (SD) Vd per kilogram TBW lower in obese vs normal-weight children (0.20 [0.05] vs 0.28 [0.07] L/kg; P o 0.01)

(continued)

J.G. Kendrick et al.

Aged 2–18 y, normal renal function, non-ICU, gentamicin with Cpk and Ctr levels



Cefazolin 25 mg/kg IV over 30 minutes

Mean (SD) amoxicillin dose for obese vs normal-weight children Z20 kg similar (40.8 vs 40.3 mg/kg/d; P ¼ 0.9)

Conclusions

Study and Design Moffett et al,48 retrospective cohort study

Drug(s)



Vancomycin

Patients





Miller et al,49 retrospective cohort study



Vancomycin

  

Heble et al,50 retrospective cohort study



Vancomycin





24 obese (BMI Z95th %) and 24 normal-weight (BMI 25th– 75th %) children matched for age and vancomycin dosing schedule (frequency of administration)

Methods

 

Vancomycin doses and serum concentrations compared between obese and normal-weight children PK parameters calculated for 4 obese children

Aged 2–17 y (mean, 7 y), normal renal function, nonICU, Ctr drawn appropriately

23 overweight (BMI, 85th– 94th %), 35 obese (BMI Z95th %) and 129 normal-weight (BMI o85th %) children



Vancomycin doses and serum concentrations compared between obese/overweight and normal-weight children

Aged 2–17 y; normal renal function, vancomycin Ctr drawn appropriately

Age 2–18 y (mean, 9 y), normal renal function, nonICU, vancomycin Ctr drawn appropriately

   

Obese/overweight matched 2.5 to 1 for age and sex

21 overweight (BMI, 85th– 94th %), 21 obese (BMI Z95th %), and 84 normalweight (BMI, 5th–84th %) children matched by age and dosing regimen

Results

  

 

Children received empiric weightand age-based vancomycin doses Vancomycin doses and serum concentrations compared between obese, overweight, and normal-weight children

   

Mean (SD) initial vancomycin dose lower obese vs normal-weight children (14.1 [1.5] vs 14.9 [0.9 mg/kg]; P ¼ 0.03)

Conclusions



Obese children had similar Ctr as normal-weight children despite marginally lower empiric doses per kilogram TBW

Mean (SD) Ctr obese vs normal-weight similar (6.9 [4.3] vs 4.8 [3.1] mg/L; P ¼ 0.052) t½, 2.5–3 h Vd, 0.19–0.55 L/kg Mean (SD) initial vancomycin dose similar between obese/overweight and normal-weight (16.6 [3.9] vs 17.2 [4.1] mg/kg; P ¼ 0.3)



Overweight/obese children receiving similar vancomycin doses per kilogram TBW have higher Ctr vs normal-weight children

Mean (SD) vancomycin Ctr higher in obese/overweight vs normal-weight (9.6 [8.9] vs 7.4 [5.7] mg/L; P ¼ 0.03) No difference in % vancomycin regimens that produced target Ctr between obese/overweight and normal-weight No statistical difference in milligram/ kilogram TBW doses between obese, overweight, and normal-weight Median initial Ctr higher in obese/ overweight vs normal-weight children (14.4 vs 10.5 mg/L; P o 0.001)

 

Vancomycin doses were not adjusted for overweight or obesity Obese and overweight children had higher Ctr and are more likely to be above target than normalweight children

No difference in the percentage of patients within target vancomycin Ctr (10–20 mg/L)

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Obese and overweight children more likely above target (17% vs 2%) and normal-weight children more likely below target (51% vs 19%)

(continued)

Clinical Therapeutics

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Table II. (continued).

September 2015

Multivariate analysis: higher baseline BMI z scores were associated with lower response to therapy: every 1 SD increase in BMI z score was associated with a 12% reduction in response to therapy for Multivariate analysis adjusted ribavirin use and HCV genotype





Examined association between BMI and response to therapy (SVR, undetectable HCV at 24 weeks’ posttreatment)

 Overweight was defined as BMI 485th %



Aged 0–20 y (median, 13 y); IFN for hepatitis C

BMI ¼ body mass index; CL ¼ clearance; Cpk ¼ peak concentration; Ctr ¼ trough concentration; HCV ¼ hepatitis C virus; IBW ¼ ideal body weight; ICU ¼ intensive care unit; IFN ¼ interferon; PK ¼ pharmacokinetic; SVR ¼ sustained virologic response; TBW ¼ total body weight; Vss ¼ volume of distribution at steady-state.

Overweight children do not seem to respond as well to IFN Univariate analysis: greater percentage of overweight children in the nonresponder group (42%) vs the responder group (19%)

IFN 3 million units/m2 (maximum, 5 million units) SC 3 times per week or pegylated IFN alfa 2α 180 mg/1.73 m2 (maximum, 180 mg) SC once weekly, both with or without ribavirin 15 mg/ kg/d orally 62 children and young adults IFN

Antiviral agents DelgadoBorrego et al,78 retrospective cohort study



Drug(s) Study and Design

Table II. (continued).

 

Patients



Methods



Results



Conclusions

J.G. Kendrick et al. equation to predict Vss of tobramycin in obese children: Vss ¼ 0.261  {IBW (kg) þ 0.4  [TBW (kg) – IBW (kg)]}. Comparing their equation with calculated pharmacokinetic parameters in the obese children, the difference was 6.8%. Choi et al46 compared gentamicin levels and pharmacokinetic parameters in 25 obese children and 25 normal-weight children (Table II). The calculated ke and t½ were similar between obese and normal-weight children; however, Vd was lower in obese children. Although the authors were not able to measure CL, the similarity in ke and t½ suggests that CL per kilogram TBW may be lower in obese children. There were no differences in nephrotoxicity, duration of hospital stay, or gentamicin therapy between groups. Based on these studies, it is unclear if gentamicin and tobramycin’s CL per TBW in obese children is similar to or lower than normal-weight children. This suggests that the total daily dose per kilogram TBW could be based on TBW or on ABW ¼ IBW þ 0.4 (TBW – IBW), similar to adults.12 Ross et al36 suggest using ABW to dose gentamicin and tobramycin in critically ill obese children. Given that aminoglycoside concentrations are typically measured in practice, empiric dosing based on TBW or ABW would be appropriate, taking into account patient-specific factors such as renal function, illness severity, and extent of obesity (Table III). Vancomycin Vancomycin distributes widely into body tissues and fluid and is eliminated primarily by glomerular filtration. In children, the Vd for vancomycin is 0.26 to 1.05 L/kg, and t½ varies from 6 to 10 hours in neonates and 2 to 4 hours in infants and children.47 Three retrospective studies have examined vancomycin dosing and serum trough concentrations in overweight and/or obese children compared with normal-weight children. Moffett et al48 compared empiric vancomycin doses and serum trough concentrations (Ctr) in 24 obese and 24 normal-weight children (Table II). Most children received vancomycin at 8-hour intervals. Despite receiving lower empiric doses (difference, 0.8 mg/kg), obese children had similar Ctr levels. In the 4 obese children who had vancomycin peak and trough concentrations, Vd and t½ were similar to published values in children.

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Clinical Therapeutics

Table III. Summary of pharmacokinetic parameters and recommendations for dosing in obese children. Drug Antineoplastic agents Busulfan65,67 Cytarabine61 Daunorubicin71 Doxorubicin72,74 Etoposide61,72 Methotrexate61 Teniposide61 Antibiotics Aminoglycosides32,46 Cefazolin32 Vancomycin48–50

AUC 2 Not reported Not Not Not Not

reported reported reported reported

Not reported Not reported Not reported

CL (L/h/kg) 2 2 2 2 2 2 2

(L/h/m2) (L/h/m2) (L/h/m2) (L/h/m2) (L/h/m2) (L/h/m2)

2 2 Not reported

Vd (L/kg)

Initial Dosing

Not reported Not reported 2 (L/m2) 2 (L/m2) Not reported Not reported Not reported

Actual Actual Actual Actual Actual Actual Actual

BSA BSA BSA BSA BSA BSA BSA

↓ 2 2

TBW or ABW TBW TBW

2 = no relative difference, compared with normal-weight; ↓ = relatively lower compared with normal-weight; ABW = adjusted body weight; BSA = body surface area; CL = clearance; TBW = total body weight.

Miller et al49 compared vancomycin doses and Ctr in 23 overweight, 35 obese, and 129 normal-weight children (Table II). Overweight/obese children received similar vancomycin doses but had higher Ctr levels compared with normal-weight children. There was no difference between overweight/obese children and normal-weight children in the percentage of concentrations within target. There was no difference in occurrence of nephrotoxicity or red man syndrome between groups. Heble et al50 compared 21 overweight children and 21 obese children versus 84 normal-weight children who were receiving vancomycin (Table II). There was no statistical difference in milligram per kilogram TBW doses between obese, overweight, and normalweight children, suggesting that there was no dose adjustment for obesity. Median initial trough levels were higher in the obese/overweight children compared with the normal-weight children. Although there was no difference in the percentage of patients within target vancomycin trough (10–20 mg/L) between obese, overweight, and normal-weight children, obese and overweight children were more likely to be above target, and normal-weight children were more likely to be below target. Based on the aforementioned studies, it seems that obese and overweight children achieve higher

1906

vancomycin trough concentrations at similar milligram per kilogram TBW doses than their normalweight counterparts, but that there is no difference in the percentage of patients who are within target range. Given that vancomycin serum concentrations are typically monitored in clinical practice, dosing obese and overweight children based on TBW seems reasonable until a better size descriptor is available (Table III).

Anticoagulant Agents Heparin Heparin is highly bound to plasma proteins, and its Vd approximates that of blood volume.33 It is cleared primarily via the reticuloendothelial system and endothelial cells and minimally by the liver and kidneys. Two retrospective studies examined the impact of obesity on heparin dosing in children. Moffett et al51 studied 39 obese children and 39 normal-weight children who received an intravenous heparin bolus for cardiac catheterization (Table IV). There was no difference in heparin bolus dose per kilogram TBW, activated clotting time (ACT), or need for additional heparin boluses between the obese and normal-weight children. The authors noted that results were not what they expected and that ACT may not be the optimal marker of heparin response.

Volume 37 Number 9

September 2015

Table IV. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of anticoagulant agents. Study and Design Moffett et al,51 retrospective cohort study

Taylor et al,52 retrospective cohort study

Drug(s)



Heparin

Patients







Heparin

 

39 obese (BMI Z95th %) and 39 normal-weight (BMI o95th %) children matched by age, sex, and catheterization procedure

Methods



Compared heparin dose and ACT between obese and normal-weight children

 

Aged 2–18 y (mean, 10 y), heparin bolus for cardiac catheterization, Z1 ACT within 120 minutes of heparin bolus 25 obese (BMI Z95th %) and 25 normal-weight (BMI, 25th–75th %) children

Results

 

Compared heparin dose and aPTT or anti-Xa between obese and normalweight children

Aged 2–18 y (mean, 12 y), continuous heparin infusion, Z1 aPTT or antiXa at least 4 hours after start of heparin infusion

   

  

Enoxaparin

  

Case 1: 16-year-old male; BMI, 105.9 kg/m2 Case 2: 16-year-old male; BMI, 95.7 kg/m2

1907

Case 3: 11-year-old male; BMI, 29.9 kg/m2

 

Enoxaparin prophylaxis during hospitalization All children initiated on usual adult enoxaparin prophylactic dose 40 mg SC daily but required dosage increases to achieve target anti-Xa concentrations (0.1–0.3 U/L)

  



Obese children receive similar doses and have similar ACT responses compared with normal-weight children

No difference in % change in ACT from baseline between obese and normalweight children (196 [106] and 165 [97] %; P ¼ 0.17) No difference in need for 41 heparin bolus between obese and normalweight children (6 and 8; P ¼ 0.4) Mean (SD) initial heparin dose lower in obese vs normal-weight (17.4 [4.2] vs 20.2 [3.3] U/kg/h; P ¼ 0.013)



Mean (SD) maintenance heparin dose lower in obese vs normal-weight (19.1 [6.7] vs 24.3 [9.6] U/kg/h; P ¼ 0.033)

Obese children require lower heparin infusion dose per kilogram TBW to achieve target aPTT or anti-Xa concentrations

Mean (SD) initial anti-Xa activity higher in obese vs normal-weight (0.45 [0.32] vs 0.29 [0.19] U/mL; P ¼ 0.045) Mean (SD) time to achieve 2 therapeutic anti-Xa concentrations (0.35–0.7 U/L) shorter in obese vs normal-weight (27.3 [17.7] vs 44 [31.7] hours; P ¼ 0.045) Mean time to achieve therapeutic aPTT was not different No difference in % of patients with treatment interruption for supratherapeutic aPTT or anti-Xa concentration or bleeding Case 1: 90–100 mg SC every 12 hours (0.28–0.33 mg/kg/dose) Case 2: 45 mg SC every 12 hours (0.15 mg/kg/dose) Case 3: 40 mg SC every 12 hours (0.49 mg/kg/dose)



Enoxaparin dose required to achieve target anti-Xa concentrations for prophylaxis lower than the recommended empiric pediatric dose but higher than adult doses in 2 of the 3 patients

(continued)

J.G. Kendrick et al.

Lewis et al,53 case report

Mean (SD) heparin dose for obese vs normal-weight children was similar (63.6 [23.6] vs 72.3 [24.9] U/kg; P ¼ 0.12)

Conclusions

Study and Design Richard et al,54 retrospective cohort study

Moffett et al,55 retrospective cohort study

Drug(s)



Enoxaparin

Patients







Warfarin



 

30 obese (BMI Z95th %) and 30 normal-weight (BMI, 25th–75th %) children matched based on age, sex, and acuity of care

Methods



Compared enoxaparin dosing and anti-Xa levels between obese and normal-weight children

Aged 2–18 y (mean, 11 y), enoxaparin treatment doses (1 mg/kg SC every 12 hours to target anti-Xa 0.5–1 U/L), anti-Xa measurement 4 to 6 hours after the second dose

10 obese (BMI Z95th %) and 20 normal-weight (BMI, o95th %) children matched based on age and sex Aged 2–18 y (mean, 14 y), warfarin Excluded Fontan procedure or mechanical circulatory support

Results

   

  

Empiric warfarin dose 0.2 mg/kg/d (maximum, 5 mg) or 0.1 mg/kg/d (maximum, 2.5 mg) if drug interaction Doses were adjusted according to the hospital’s algorithm Compared obese vs normal-weight children warfarin doses and INR



 

Initial enoxaparin dosing no different in obese vs normal-weight children

Conclusions



Mean (SD) first anti-Xa concentration was higher in obese vs normal-weight children (0.67 [0.27] vs 0.53 [0.24] U/L; P ¼ 0.028)

Obese children require lower enoxaparin dose per kilogram TBW to achieve therapeutic anti-Xa concentrations

Mean (SD) therapeutic dose lower was in obese vs normal-weight children (0.81 [0.2] vs 1.1 [0.4] mg/kg; P ¼ 0.005) No statistical difference in % of obese vs normal-weight children with supratherapeutic anti-Xa during treatment (70% vs 47%; P ¼ 0.12) Lower mean (SD) empiric and adjusted warfarin doses for obese vs normal-weight children (0.06 [0.02] vs 0.11 [0.04], P o 0.01, and 0.09 [0.04] vs 0.13 [0.05] mg/kg/d, P ¼ 0.04)



Obese children require lower warfarin doses per kilogram TBW, but empiric doses that are capped at 5 or 2.5 mg may prolong time to therapeutic INR

Median time (range) to therapeutic INR was longer in obese vs normalweight children (6 [4–28] vs 3 [1–10] days; P o 0.01) No statistical difference in % of obese vs normal-weight children with supratherapeutic INR during treatment (10% vs 40%; P ¼ 0.09

ACT ¼ activated clotting time; aPTT ¼ activated partial thromboplastin time; BMI ¼ body mass index; INR ¼ international normalized ratio; TBW ¼ total body weight.

Clinical Therapeutics

1908

Table IV. (continued).

Volume 37 Number 9

J.G. Kendrick et al. Taylor et al52 evaluated 25 obese and 25 normalweight children who received heparin intravenous infusions (Table IV). Obese children received lower initial and maintenance doses of heparin and had higher initial anti-Xa levels than normal-weight children. However, obese children achieved therapeutic anti-Xa levels faster than normal-weight children. There was no difference in time to therapeutic activated partial thromboplastin time (aPTT) or in treatment interruptions. Only 1 bleeding event occurred in a normal-weight child. A limitation of this study was that the authors did not describe the timing of the anti-Xa or aPTT levels. The authors noted that differences between anti-Xa concentration and aPTT suggest a lack of agreement in assays. Limitations to both studies included small sample size and inability to perform multivariate analysis or

correct for multiple comparisons. The ability to interpret these studies may be limited by the different assays used. It does seem, however, that obese children should receive a heparin bolus dose based on TBW but that they may require lower heparin infusion doses (Table V). Ross et al36 suggest dosing heparin infusions by using ABW (cofactor of 0.4) in critically ill obese children based on the hydrophilic nature of heparin and the water content of adipose tissue. Enoxaparin Enoxaparin is the low-molecular-weight heparin that is most commonly used in children. It is primarily eliminated by the kidneys.33 Lewis et al53 reported on 3 hospitalized children who received prophylactic enoxaparin (Table IV). All

Table V. Summary of pharmacodynamic parameters and recommendations for dosing in obese children. Drug Anticoagulant agents Heparin51,52

Pharmacodynamic Parameter

Enoxaparin53,54

Anti-Xa ↑ aPTT ACT 2 Anti-Xa ↑

Warfarin55

↑ time to therapeutic INR

Antiviral agent Interferon78 Antihypertensive agents ACE inhibitor or ARB79,80 CCB79

Neuromuscular blocking agent Succinylcholine81 Vitamins Vitamin D86–88

Initial Dosing TBW

TBW; recommend against empiric adult dose for prophylaxis TBW; recommend against capping initial dose at 5 mg (or 2.5 mg if drug interaction)

↓SVR

TBW; optimal dose unclear

BP response 2 BP response ↓

Empiric low dose Empiric dose; may need to be increased; combination BP lowering therapy may be required

Baseline muscle twitch 2

TBW

2 or ↓ 1,25(OH)2D and 25 (OH) D

Empiric dose

2 = no relative difference, compared with normal-weight; ↓ = relatively lower compared with normal-weight; ↑ = relatively higher compared with normal-weight; 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; ACE = angiotensin-converting enzyme; ACT = activated clotting time; aPTT = activated partial thromboplastin time; ARB = angiotensin receptor blocker; BP = blood pressure; CCB = calcium channel blocker; INR = international normalized ratio; SVR = sustained virologic response; TBW = total body weight.

September 2015

1909

Clinical Therapeutics children were initiated on usual adult enoxaparin prophylactic doses but required dosage increases to achieve target anti-Xa concentrations. Adjusted doses were lower than the recommended empiric pediatric dose of 0.5 mg/kg TBW SC every 12 hours in 2 of the 3 patients.47 Richard et al54 studied 30 obese children and 30 normal-weight children who received enoxaparin treatment doses (Table IV). Both groups received similar initial enoxaparin doses per kilogram TBW; however, obese children had higher initial anti-Xa concentrations and required lower maintenance enoxaparin doses than normal-weight children. Both groups of children required lower doses of enoxaparin over time. The authors noted that they could not control for other factors (eg, puberty) which may affect enoxaparin dosing. From the case report and the retrospective study,53,54 it seems that obese children may require lower doses of enoxaparin per kilogram TBW than normal-weight children for treatment or prophylaxis to achieve target anti-Xa concentrations; however, standard empiric adult doses may not be appropriate. Ross et al36 suggest dosing enoxaparin using ABW (cofactor of 0.4) in critically ill obese children and titrating to effect. For enoxaparin treatment, standard pediatric empiric dosing based on TBW and monitoring anti-Xa concentrations can also be used.

Warfarin Moffett et al55 conducted a retrospective cohort study of 10 obese and 20 normal-weight children who received warfarin (Table IV). Obese children had lower empiric and adjusted warfarin doses than normal-weight children. Time to therapeutic international normalized ratio (INR) was longer in obese versus normal-weight children. There was no difference in the percentage of patients with supratherapeutic INR. Data regarding bleeding episodes and outpatient therapy were not captured. The authors noted that the small sample size precluded multivariate analysis to account for other factors affecting warfarin dose (eg, genetics, diet, drug interactions). This study suggests that although obese children may require lower doses per kilogram TBW than normalweight children, capping initial doses at 5 mg (or 2.5 mg in case of drug interaction) may unnecessarily prolong the time to achieve a therapeutic INR.

1910

Antineoplastic Agents Doses of chemotherapy are commonly calculated based on a patient’s BSA, using TBW. In 2012, the American Society of Clinical Oncology published guidelines suggesting that obese adults receive curative chemotherapy based on TBW; this recommendation was based primarily on evidence that alternate size descriptors could result in underdosing and lead to less effective therapy and that dosing based on TBW was not routinely associated with excess toxicity.56–58 We found no similar guidelines for obese children. A retrospective cohort study by Baillargeon et al59 comparing chemotherapy dose calculations between obese and normal-weight children with leukemia found that 7% of obese children received less than the protocol-specified dose. Although this study did not report clinical outcomes, there are multiple cohort studies describing efficacy and safety outcomes in obese versus normal-weight children receiving treatment for acute myeloid leukemia or acute lymphocytic leukemia (ALL) (Table VI).60–64 It seems that obesity may be associated with lower survival in children with leukemia, despite their receiving chemotherapy doses based on TBW.60–64 Association between obesity and drug toxicity in children is unclear based on these retrospective studies. Large prospective studies would help to better elucidate the impact of obesity on clinical outcome in children with cancer. One must also consider the pharmacokinetics of chemotherapeutic agents in obese children, which are reviewed in the following discussion (Table III). Busulfan Busulfan is a hydrophilic drug that is minimally protein bound and primarily metabolized by the liver. It is given orally or intravenously in preparation for stem cell transplantation.33 Two retrospective studies described busulfan pharmacokinetics in obese children. Dupuis et al65 conducted a retrospective cohort study to examine busulfan dosing in 38 children and found that busulfan doses adjusted to achieve a target AUC did not differ in children whose TBW was greater than their IBW (Table VII). An error in the busulfan gas chromatography assay that may have led to erroneously high concentrations was later reported.66 Browning et al67 conducted a retrospective cohort study of 68 children receiving busulfan, 32% of whom were overweight (Table VII). Overweight children

Volume 37 Number 9

September 2015

Table VI. Summary of studies describing the effect of obesity on cancer outcomes. Study and Design ALL Hijiya et al,61 retrospective cohort study

Galelete et al,62 retrospective cohort study

Butturini et al,63 retrospective cohort study

AML Inaba et al,60 retrospective cohort study





 

 

  

621 children age 41 y who received treatment for ALL

181 children, 93% o10 y, 36% overweight or obese (BMI 1 or 2 SDs above z score for age), treatment for ALL

343 obese (BMI Z95th %) and 3917 normal-weight children, aged 0–20 y, treatment for ALL Excluded Down syndrome or central nervous system disease

Children and young adults aged 2–20 years who received treatment for AML Overweight, obese, and normal-weight defined as BMI 85 to o95th %, Z95th %, and 5 to o85th %

768 children and young adults, aged 0–20 years; treatment for AML Excluded Down syndrome Overweight and normal-weight defined as BMI Z95th % and 11th–94th % (for children aged 42 y) or weight-for-length Z95th % and 11th–94th % (for children aged 1–2 y)

Chemotherapy and Methods

   

    

 

Chemotherapy doses based calculated by using TBW

on

Efficacy

BSA



Efficacy analysis, but not safety analysis, was adjusted for potential confounders of age, sex, WBC at diagnosis, immunophenotype, and DNA index BSA



Multivariate analysis adjusted for age, WBC count, and response after first week of treatment



Chemotherapy doses based calculated by using TBW

on

Chemotherapy doses were based on BSA using TBW in 98.5% of obese children, except vincristine, which had a maximum dose of 2 mg Multivariate analysis adjusted for age, WBC count, race, and bone marrow response at day 7 Toxicity not uniformly reported Chemotherapy doses not modified on the basis of BMI Multivariate regression with age, leukocyte count, French-American-British classification as predictors and stratified according to study protocol Chemotherapy was dosed based on TBW or BSA calculated by using TBW Multivariate analysis adjusted for age, race, WBC count, cytogenetics, and allogeneic bone marrow transplant

 



 

No significant association between BMI and complete remission, OS, cumulative incidence of relapse

Five-year EFS lower in overweight/obese children vs normal-weight children (61% vs 81%; P ¼ 0.03)

Safety





No significant association between BMI and grade 3 or 4 toxicity

Not reported

Obesity independently associated with lower 5year EFS (HR, 1.92 [95% CI, 1.42–2.6]) Obesity associated with lower 5-year EFS (HR, 1.36 [95% CI, 1.04–1.77])



Obesity associated with more relapses (HR, 1.29 [95% CI, 1.02–1.56])

Overweight/obese children had lower 5-year OS vs normal-weight children (HR, 1.84 [95% CI, 1.22–2.78])

 

Obesity had no effect on length of interval between diagnosis and completion of fourth phase, hospitalization, death during induction, or death secondary to toxicity

Overweight/obese children had more grade 2 or 3 infections Treatment-related mortality higher overweight/obese children compared with normal-weight children

in

No statistical difference in EFS (HR, 1.4 [0.96–2.04]) Overweight children had lower OS than normalweight children (HR, 1.88 [95% CI, 1.25–2.83])

 

Treatment-related mortality higher in overweight children (HR, 3.49 [95% CI, 1.99–6.1]) Overweight children more likely to die before first remission, with most common cause being infection

1911

ALL ¼ acute lymphocytic leukemia; AML ¼ acute myeloid leukemia; BMI ¼ body mass index; BSA ¼ body surface area; EFS ¼ event-free survival; HR ¼ hazard ratio; OS ¼ overall survival; TBW ¼ total body weight; WBC ¼ white blood cell count.

J.G. Kendrick et al.

Lange et al,64 retrospective cohort study

Patients

Study and Design Dupuis et al,65 retrospective cohort study

Drug(s)



Busulfan

Patients

 

38 children 0.2–17.5 y (median, 5.7 y)

Methods

   

Browning et al,67 retrospective cohort study



Busulfan

  

68 children and young adults Aged 0–21 y (mean, 7.1 y), SCT preparation with busulfan and either fludarabine and rabbit ATG or extracorporeal photophoresis 32% overweight (BMI Z85th %)

    

Hijiya et al,61 retrospective cohort study

   

Cytarabine Etoposide

 

Methotrexate Teniposide



621 children Aged 41 y, ALL treatment with cytarabine, methotrexate, teniposide, etoposide 8.9% obese (BMI Z95th %)



Volume 37 Number 9

       

Oral or nasogastric busulfan 40 mg/m2 based on BSA calculated from TBW

Results



Whole blood busulfan concentrations at 1, 1.5, and 6 hours

Adjusted busulfan dose was not different in children whose TBW was greater than their IBW

Conclusions



TBW is appropriate for initial busulfan dosing

AUC calculated based on limited sampling strategy Subsequent busulfan doses adjusted to achieve a target AUC 900–1400 μM/min Test dose busulfan 0.8 mg/kg TBW



Whole blood busulfan concentrations at 3, 3.5, 5, and 7 hours after start of test dose Expected AUC for test dose 800–1200 μM/min. Further regimen doses based on pharmacokinetic parameters to achieve target AUC 4000 or 5000 μM/min Compared busulfan dosing and AUC for overweight vs normal-weight children

 

Compared busulfan dosing based on PK vs package insert (dose based on ABW ¼ IBW þ 0.25(TBW – IBW) Chemotherapy doses based on BSA calculated by using TBW, then adjusted based on CL Cytarabine 300 mg/m2 Etoposide 300 mg/m2 6-Mercaptopurine PO 75 mg/m2 High-dose methotrexate 1500–5000 mg/m2



Lower mean (SD) regimen doses per kilogram TBW for overweight vs normal-weight children (2.9 [1.1] vs 4.0 [1.1] mg/kg/d; P ¼ 0.001) No association between BMI and AUC being under or over target for test dose





Regimen dose based on PK vs package insert dose for overweight children achieved target AUC for 84% vs 47%

Mean cytarabine, etoposide, methotrexate, and teniposide CL not significantly different between obese and normal-weight children, after adjusting for known confounders including age (o10 y or Z10 y), course of treatment, and study protocol



TBW is appropriate for the test dose; adjust regimen doses based on PK parameters Dose based on ABW does not seem to achieve target AUC for overweight children

Cytarabine, etoposide, methotrexate, and teniposide doses based on BSA calculated using TBW are appropriate

Teniposide 200–375 mg/m2 Compared safety, efficacy, and PK parameters between obese and normal-weight children PK parameters derived from plasma– concentration time profiles by using noncompartmental analysis CL calculated by multiplying Vd by ke

(continued)

Clinical Therapeutics

1912

Table VII. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antineoplastic agents.

September 2015

Table VII. (continued). Study and Design Thompson et al,71 PK study

Drug(s)



Daunorubicin

Patients

  

Ritzmo et al,72 case report

 

Doxorubicin



Etoposide

98 children Aged 1–21 y (median, 12 y), daunorubicin over 1 or 2 days as part of chemotherapy regimen

Methods

 

16 obese children (BMI Z95th %); 15 children with body fat 430% Morbidly obese 14 year-old boy (weight, 137 kg; height, 172 cm; BMI, 46.3 kg/m2; BSA, 2.56 m2) with Hodgkin’s lymphoma

  

  Thompson et al,74 PK study



Doxorubicin

  

22 children Aged 1–21 y (median, 15 y), doxorubicin over 1 or 2 days as part of chemotherapy regimen 6 children with body fat 430%; 2 children overweight (BMI 485th %)

 

Results

Daunorubicin dosing not described



PK parameters derived from plasma– concentration time profiles using 2compartment model for daunorubicin and 1-compartment model for daunorubicinol



Chemotherapy doses based on adjusted BSA 1.91 m2 (derived from the expected upper limit of weight for height) Doxorubicin 40 mg/m2 (corresponding to 30 mg/m2 actual BSA) IV over 4 hours on days 1 and 15. Courses were separated by 2 weeks Plasma concentrations of doxorubicin and its metabolite, doxorubicinol, immediately before end of infusion on day 1 of the first course and days 1 and 15 of the second course

  

Daunorubicin and daunorubicinol Vd (L/m2) and CL (L/h/m2) similar in obese vs normal-weight children

Conclusions



Daunorubicin and daunorubicinol Vd and CL similar in children with body fat o30% and 430% Doxorubicin and doxorubicinol plasma concentrations 202, 181, and 162 ng/mL and 11.8, 16.9, and 14.2 ng/mL, respectively Median doxorubicin CL 476 mL/min/m2

 

Median etoposide CL 16.1 mL/min/m2 and t½ 3.6 hours

Daunorubicin dose based on BSA calculated by using TBW seems appropriate

Doxorubicin CL is similar to reference values for normalweight children Etoposide CL and t½ are similar to reference values for normal-weight children

Etoposide 125 mg/m2 (corresponding to 94 mg/m2 actual BSA) over 2 hours on days 3 to 7 Etoposide plasma concentrations on day 3 immediately before dosing and at 1, 2, 3, 6, and 12 hours after end of dosing Doxorubicin dosed based on actual BSA PK parameters derived from plasma– concentration time profiles by using noncompartmental analysis

 

Doxorubicin Vd and CL similar children with body fat o30% and 430%



Doxorubicin dose based on BSA calculated by using TBW seems appropriate

Mean doxorubicinol Vd and CL higher in children with body fat 430% vs r30% (37.2 vs 64.8 L/h/m2; [P ¼ 0.03] and (802 vs 1450 L/m2 [P ¼ 0.02])

1913

(continued)

J.G. Kendrick et al.



Doxorubicin and doxorubicinol Vd (L/m2) and CL (L/h/m2) similar in overweight vs normal-weight children

1914

Folinic acid rescue and intravenous fluids containing sodium bicarbonate were administered, and the child improved



Methotrexate concentration drawn 4 days after the dose was 2.9 μmol/L (supratherapeutic)



Renogram suggested acute tubular necrosis

 Doses escalated to 250 mg/m2



ABW ¼ adjusted body weight; ALL ¼ acute lymphocytic leukemia; ATG ¼ antithymocyte globulin; BMI ¼ body mass index; BSA ¼ body surface area; CL ¼ clearance; GFR ¼ glomerular filtration rate; IBW ¼ ideal body weight; PK ¼ pharmacokinetic; PO ¼ orally; SCr ¼ serum creatinine; SCT ¼ stem cell transplantation; TBW ¼ total body weight.

Role of obesity in development of nephrotoxicity is not clear Three days after the 250-mg/m2 dose, SCr was 2.8 mg/dL (baseline, 0.6 mg/dL) and GFR was 25 mL/min/1.73 m2 Initial methotrexate dose 100 mg/m2, based on calculated BSA of 2.3 m2 using TBW

16-year-old obese boy (weight, 110 kg; height, 170 cm; BMI, 38.1 kg/m2) who received methotrexate as part of his ALL treatment Methotrexate Sauer et al,76 case report



Drug(s) Study and Design

Table VII. (continued).



Patients



Methods



Results



Conclusions

Clinical Therapeutics received lower regimen doses per kilogram TBW compared with children with a BMI in the 25th to 84th percentile. There was no association, however, between BMI and AUC being under or over target for the test dose. Limitations to these 2 studies65,67 are inherent to the small sample size; the authors were not able to perform multivariate analysis or adjust for potential confounders such as drug interaction, age, and malignancy. From these studies, it seems that initial busulfan doses should be administered based on TBW (as opposed to IBW or ABW) for overweight or obese children (Table III). Pharmacokinetic analysis can help clinicians adjust subsequent doses to achieve target AUC. Cytarabine Hijiya et al61 conducted a retrospective cohort study of 621 children (aged 41 year) who received treatment for ALL (Table VII). Cytarabine, methotrexate, and teniposide dosage was adjusted based on drug CL, and pharmacokinetic data were reported previously.68–70 Pharmacokinetic data were described for cytarabine, methotrexate, teniposide, and etoposide. Mean cytarabine CL was not significantly different between overweight, risk of overweight, and normal-weight children, after adjusting for known confounders including age (o10 years or Z10 years), course of treatment, and study protocol. This study suggests that cytarabine can be dosed based on BSA calculated by using TBW. Results for methotrexate, teniposide, and etoposide are described later. Daunorubicin Thompson et al71 studied daunorubicin pharmacokinetics in 98 children, 16 of whom were obese and 15 of whom had body fat 430% (Table VII). Daunorubicin and daunorubicinol Vd and CL were similar between obese and normal-weight children as well as for children with body fat 430%. Although the authors did not describe daunorubicin dosing, Vd and CL were expressed as a function of BSA. This study suggests that doxorubicin should be dosed based on BSA calculated by using TBW (Table III). Doxorubicin Ritzmo et al72 reported on a morbidly obese boy with Hodgkin’s lymphoma who received treatment

Volume 37 Number 9

J.G. Kendrick et al. with doxorubicin and etoposide (Table VII). Doses were provided based on an adjusted BSA. Doxorubicin and doxorubicinol plasma concentration and doxorubicin CL were similar to those of normal-weight children from a previous study.73 No toxicity was observed, and the patient’s ECG and echocardiography were normal at 2 months and 2 years after treatment. Based on the calculated doxorubicin CL, the dose based on BSA calculated by using his TBW would have been appropriate. Thompson et al74 studied doxorubicin pharmacokinetics in 22 children, 2 of whom were overweight and 6 of whom had body fat 430% (Table VII). Doxorubicin and doxorubicinol Vd and CL were similar between overweight and normalweight children. This study, although limited by the small number of overweight patients, also suggests that doxorubicin should be dosed based on BSA calculated by using TBW (Table III). Etoposide In the case report by Ritzmo et al,72 etoposide was dosed based on an adjusted BSA. Etoposide CL and t½ were similar to previously published values for 16 normal-weight children.75 In the retrospective cohort study by Hijiya et al61 described earlier, there was no significant difference in mean etoposide CL between the overweight, risk of overweight, and normal-weight children. Both this study and the case report suggest that etoposide should be dosed based on BSA calculated by using TBW in obese children. Methotrexate Sauer et al76 published a case report of a 16-yearold obese boy who received intermediate-dose methotrexate as part of his treatment for ALL (Table VII). Three days after the 250-mg/m2 dose, the child developed renal injury. There have been similar reports of renal injury after administration of intermediate-dose methotrexate in normal-weight adults.77 Given that other risk factors for renal injury were not reported, the role of obesity in methotrexate toxicity is unclear in this case. In the retrospective cohort study by Hijiya et al,61 there was no significant difference in mean CL of highdose methotrexate between overweight, risk of overweight, and normal-weight children. This finding suggests that methotrexate should be dosed based on BSA calculated by using TBW. Monitoring clinically

September 2015

for signs of toxicity and measuring serum methotrexate concentrations as warranted seem reasonable. Teniposide In the retrospective cohort study by Hijiya et al,61 there was no significant difference in mean CL of teniposide between overweight, risk of overweight, and normal-weight children. This finding suggests that teniposide should be dosed based on BSA calculated using TBW.

Antiviral Agents Delgado-Borrego et al78 conducted a retrospective cohort study of children and young adults who were treated with interferon for hepatitis C virus infection (Table II). The mean dose per kilogram TBW or percentage of patients receiving the maximum dose was not described. In multivariate analysis, adjusted for ribavirin use and genotype, higher baseline BMI z scores were associated with lower response to therapy. Currently, it is unclear if an alternative dosing strategy should be used for interferon in overweight children.

Antihypertensive Agents Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Hanafy et al79 conductive a retrospective cohort study of 48 children treated with an angiotensin II receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, or a calcium channel blocker (CCB) for hypertension associated with renal disease (Table VIII). The mean doses of medications were similar between groups. Obesity did not affect response to therapy in multivariate analyses. The small number of children receiving ACE inhibitors or ARBs is a limitation to this study; however, it suggests that obese and normal-weight children may have similar reductions in blood pressure when given the same dose of an ACE inhibitor or an ARB. Meyers et al80 conducted a post-hoc analysis of their previous randomized, double-blind trial to compare the blood pressure–lowering effects of valsartan in obese and normal-weight children (Table VIII). Although the valsartan dose per kilogram TBW was lower in obese children compared with normal-weight children, similar reductions in blood pressure were achieved in obese and normal-weight children. Adverse events were similar between groups. This study suggests that valsartan is similarly effective in obese

1915

Study and Design Hanafy et al,79 retrospective cohort study

Drug(s)

  

ACE-I

Patients



ARB CCB



25 obese (BMI Z95th % for age 2–18 y and weight Z95th % for age o2 y) and 23 normal-weight children Aged 0–18 y (mean, 8 y); ARB, ACE-I, or CCB for hypertension associated with renal disease

Methods

    

Meyers et al,80 post-hoc analysis of previous RCT



Valsartan

 

142 obese (BMI Z95th % or BMI z score Z1.54) and 119 normal-weight children Aged 6–16 y, weight Z20 kg, MSSBP Z95th % for age, sex, and height

 

Compared response to therapy (responder defined as 410% reduction in systolic and/or diastolic blood pressure from baseline) Multivariate analysis tested for covariates: age, sex, obesity, nephrotic syndrome and corticosteroid use 8 children received ramipril; 7 children received other ACE-I or ARB 9 children received amlodipine, 33 children received nifedipine

Results

   

9 children received combination ACE-I or ARB with CCB RCT: randomized to low-, medium-, or highdose valsartan for 2 weeks (subjects o35 kg received 10, 40, or 80 mg PO daily and those Z35 kg received 20, 80, or 160 mg PO daily) Post-hoc analysis compared valsartan dosing and response to therapy (target MSSBP defined as o95% for age, sex, and height)

   

Mean doses of ACE-Is, ARBs, or CCBs (mg/m2) similar in obese vs normal-weight % reduction in SBP similar in obese vs normal-weight Obesity did not affect response to ACE-I or ARB therapy in multivariate analysis

Conclusions





Obesity had a significant effect on SBP response (OR, 12.26 [CI, 1.2– 122]) to CCB in the multivariate analysis Median (range) valsartan dose lower in obese vs normal-weight children (0.9 [0.3–4] mg/kg/d vs 1.7 [0.1– 4.6] mg/kg/d; P value not reported)



Obese children receiving similar mg/ m2 doses of ACE-Is or ARBs have similar response to therapy vs normal-weight children Obese children receiving similar mg/ m2 doses of CCBs may have poorer response to therapy vs normal-weight children

Valsartan is similarly effective in obese vs normal-weight children despite lower doses per kilogram TBW

Similar reductions in blood pressure in obese and normal-weight children Target MSSBP achieved in 56% of obese and 44% of normal-weight children Maximal BP reduction occurred at medium-dose for obese and highdose for normal-weight children

Volume 37 Number 9

ACE-I ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; BP ¼ blood pressure; CCB ¼ calcium channel blocker; MSSBP ¼ mean sitting systolic blood pressure; OR ¼ odds ratio; PK ¼ pharmacokinetic; RCT ¼ randomized controlled trial; SBP ¼ systolic blood pressure; TBW ¼ total body weight.

Clinical Therapeutics

1916 Table VIII. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of antihypertensive agents.

J.G. Kendrick et al. and normal-weight children, despite obese children receiving a lower dose per kilogram TBW. Valsartan could be initiated at low doses and titrated to effect in both normal-weight and obese children. These studies suggest that obese children have a blood pressure–lowering response to ACE inhibitors and ARBs similar to that of normal-weight children. Although there is limited information for ACE inhibitors, it seems that these medications should be dosed similarly in obese and normal-weight children. An empiric low starting dose can be used, and the medication can then be titrated to effect (Table V).

rocuronium be dosed by using ABW (cofactors of 0.2, 0.25, and 0.25, respectively) in critically ill obese children. This recommendation was based on studies in obese adults and the potential for accumulation with prolonged use if TBW is used for dosing. Neuromuscular blocking agent response can likely be monitored clinically to assist with determination of appropriate dosing in obese children. Indication, duration of use, and patient’s organ function should be considered when dosing these agents in obese children.

Respiratory Agents Calcium Channel Blockers In the same study by Hanafy et al,79 amlodipine, short-acting nifedipine, and long-acting nifedipine were prescribed. Mean doses of CCBs were similar between the obese and the normal-weight children (Table VIII). In multivariate analysis, obesity had a significant effect on systolic blood pressure response. Although this study was small, the results suggest that obese children may require higher doses of CCBs or other medications to achieve blood pressure control.

Kwong and Jones83 reported on 2 obese children who received omalizumab 375 mg SC every 2 weeks for moderate persistent asthma, despite there being no manufacturer-recommended dose based on their weight and immunoglobulin E level (Table IX). Both children had improvements in their asthma control, and both tolerated omalizumab. This case report suggests that obese children may still derive benefit from this drug.

Vaccines Neuromuscular Blockers One dose–response study was available for the neuromuscular blocking agent succinylcholine.81 Succinylcholine, an ionized drug, is rapidly metabolized in plasma by pseudocholinesterases to succinylmonocholine, which is eliminated renally.33 To determine the potency of succinylcholine, Rose et al81 evaluated 30 obese children who received succinylcholine at doses of 100, 150, or 250 μg/kg TBW (Table I). The effective dose (ED) to depress 50% and 95% of muscle twitch (ED50 and ED95) were similar to those of 40 normal-weight children from a previous study.82 Succinylcholine had similar potency in obese and normal-weight children, and the authors suggest that it be dosed based on TBW. Ross et al36 suggested using ABW (cofactor of 0.8) to dose succinylcholine in critically ill obese children. In the study described earlier by Burke et al,34 obese children were more likely than normal-weight children to receive 410% less than the recommended dose of succinylcholine based on TBW. We found no dose–response or pharmacokinetic studies describing nondepolarizing neuromuscular blocking agents in obese children. Ross et al36 recommended that cisatracurium, pancuronium, and

September 2015

Minana et al84 studied 427 children to examine hepatitis B vaccine immune response and duration of protection in obese versus normal-weight children (Table IX). There was a weak correlation between BMI and hepatitis B surface antigen antibodies; however, all children had concentrations of these antibodies above the recommended 10 IU/L. Eliakim et al85 studied 15 overweight and 15 normal-weight age-matched control subjects to examine response to childhood immunizations (Table IX). Timing of the last tetanus vaccine relative to the study was not provided. Antitetanus immunoglobulin G concentrations were significantly lower in overweight versus normal-weight children, but all children had antitetanus immunoglobulin G concentrations above the recommended threshold of 0.1 IU/mL. It seems that obese children may have a lower response to hepatitis B and tetanus immunization than normal children; however, the clinical significance of this finding is unclear given that obese children produce antibodies at concentrations well above the recommended threshold. Overweight and obese children should continue to receive the same immunizations as normal-weight children according to local guidelines.

1917

Study and Design

Drug(s)

Respiratory agents Kwong and Jones,83 case report



Omalizumab

Patients

   

Vaccines Minana et al,84 prospective cohort study

Eliakim et al,85 retrospective cohort study





Hepatitis B vaccine

Tetanus vaccine

    

2 obese children received omalizumab for moderate persistent asthma Both receiving high-dose inhaled corticosteroid, long-acting β-agonist, and leukotriene receptor antagonist

Methods

 

Results

Omalizumab 375 mg SC every 2 weeks No manufacturer dosing for obese children

 

Volume 37 Number 9

Rajakumar et al,86 prospective cohort study



Vitamin D





Obese children may benefit from omalizumab at maximum doses

Case 1: fluticasone dose reduced and achieved complete asthma control at the end of the first year

Case 1: 14-year-old male; weight, 113 kg; IgE concentration, 459 U/mL Case 2: 13-year-old male; weight, 120 kg; IgE concentration, 677 U/mL

427 children



Mean age 12 y, hepatitis B vaccine Obese children (BMI 490th %)

15 overweight (BMI 485th %) and 15 normal-weight agematched controls Age 8–17 y (mean, 13 y), immunizations per parent report

  

Hepatitis B vaccine 20 μg intramuscularly (into deltoid) at 0, 1, and 6 months. Serum anti-HBs measured by radioimmunoassay 1 month after last immunization Tetanus report

vaccine

per

parent

Compared immunologic markers and tetanus antibodies between overweight and normal-weight children

      

Vitamin D

In first year, both children had reductions in asthma symptoms and in courses of oral steroids for exacerbations

Conclusions

21 obese (BMI 4 95th %) and 20 normal-weight (BMI 5th–75th %) children matched for age, sex, skin color, pubertal maturation

 

Vitamin D3 400 IU daily for 1 month Completed validated questionnaire

food



Weak correlation between BMI and anti-HBs concentrations (r ¼ –0.118; P ¼ 0.015)



Median anti-HBs lower in obese vs normalweight children (34,186 vs 47,186 IU/L) All children had anti-HBs concentrations above the recommended level of 10 IU/L Circulating TNF-α, IL1-β, IL1ra, IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4 not significantly different in overweight vs normal-weight



Mean (SD) IL-6 concentration higher in overweight vs normal-weight children (2.6 [1.2] pg/mL vs 1.3 [1.2] pg/mL; P o 0.05)

Obese children may have lower antibody response to hepatitis B vaccine, but clinical significance is unclear

Obese children may have lower antibody response to tetanus vaccine, but clinical significance is unclear

Mean (SD) antitetanus IgG concentration lower in overweight vs normal-weight children (2.6 [2.3] IU/mL vs 4.2 [1.9] IU/mL; P o 0.05) All children had anti-tetanus IgG concentrations above the recommended threshold of 0.1 IU/mL 25(OH)D, 1,25(OH)2D, calcium, phosphorus, albumin, PTH, markers of bone formation, and resorption similar at baseline in obese versus normal-weight children



Obese children had similar vitamin D status and response to supplementation vs normal-weight children

(continued)

Clinical Therapeutics

1918

Table IX. Summary of studies describing the pharmacokinetics, pharmacodynamics, and drug dosing of miscellaneous medications.

September 2015

Table IX. (continued). Study and Design

Drug(s)

Patients



Aged 6–10 y, African American, vitamin D supplementation

Methods



Compared vitamin D status and response to supplementation in obese vs normal-weight children

Results

  

Mark et al,87 prospective cohort study



Vitamin D

 

Aged 8–11 y (mean, 9.2 y), at risk of obesity (BMI Z30 kg/m2 or waist circumference 488 cm for girls and 102 cm for boys)



42% overweight (BMI Z85th %)

Assessed physical measurements, including dual-energy x-ray absorptiometry for fat mass, dietary intake, and plasma 25 (OH)D

   

Aguirre Castaneda et al,88 prospective cohort study



Vitamin D

 

18 obese (BMI Z95th %) and 18 normal-weight (BMI, 5th–85th %) children matched for age, sex, and season Aged 12–18 y; white; vitamin D supplementation

 

Vitamin D 2000 IU daily for 12 weeks Compared vitamin D status and response to supplementation in obese vs normal-weight children

 



Proportion of vitamin D deficiency (serum 25 [OH]D r20 ng/mL) and insufficiency (serum 25[OH]D 420 and o30 ng/mL) similar at baseline Lower mean (SD) vitamin D intake in obese vs normal-weight children during the study period (218.1 [112] IU/d vs 339 [153] IU/d) No significant difference in proportion of vitamin D deficiency or insufficiency, serum calcium, phosphorus, albumin, PTH, and bonespecific alkaline phosphatase after 1 month of vitamin D supplementation in obese versus normal-weight children

Mean (SD) dietary intake of vitamin D was 6.6 (4.3) mg/d, which was below the recommended intake of 15 mg/d



Fat mass was not associated with plasma 25(OH)D

4% of children had plasma 25(OH)D r37.5 nmol/L, defined as hypovitaminosis D % children with 25(OH)D r50 nmol/L and r75 nmol/L were 44.7% and 96.2%, respectively Multivariate analysis: season, physical activity, and milk intake associated with plasma 25(OH) D, but fat mass was not associated with plasma 25(OH)D Baseline mean 25(OH)D lower in obese vs normal-weight children (25.2 vs 28.9 ng/mL; P ¼ 0.029) Baseline prevalence of vitamin D deficiency or insufficiency (25[OH]D o30 ng/mL) higher in obese versus normal-weight children (78% vs 61%)



Obese children were more likely to have vitamin D deficiency and lower response to supplementation

Change in 25(OH)D lower in obese vs normalweight children (5.8 vs 9.8 ng/mL; P ¼ 0.019) After supplementation, prevalence of vitamin D deficiency 50% in obese and 11% in normalweight children

1919

1,25(OH)2D ¼ 1,25-dihydroxyvitamin D; 25(OH)D ¼ 25-hydroxyvitamin D; anti-HBs ¼ hepatitis B surface antigen antibodies; BMI ¼ body mass index; Ig ¼ immunoglobulin; IL ¼ interleukin; PTH ¼ parathyroid hormone; SC ¼ subcutaneous; TNF ¼ tumor necrosis factor.

J.G. Kendrick et al.



Conclusions

Clinical Therapeutics

Vitamins and Minerals Rajakumar et al86 prospectively compared vitamin D status and response to supplementation during winter months in a cohort of 21 obese and 20 normal-weight African-American children (Table IX). Obese children had similar serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D concentrations at baseline compared with normal-weight children. After 1 month of vitamin D supplementation, there was no difference in proportion of vitamin D deficiency or insufficiency between obese and normal-weight children. To assess vitamin D status, Mark et al87 conducted a prospective cohort study of children who were at risk of obesity. Fat mass was not associated with plasma 25(OH)D concentration. Aguirre Castaneda et al88 conducted a prospective cohort study of obese and normal-weight white children. Prevalence of vitamin D insufficiency or deficiency was higher in obese children at baseline and after 12 weeks of vitamin D 2000 IU daily. The authors did not collect dietary vitamin D intake information, and adherence to treatment could not be adequately assessed. The impact of obesity on vitamin D status and response to supplementation in children is not clear from the aforementioned studies. Obese children may require larger doses of vitamin D supplementation; however, doses can be adjusted according to 25(OH)D concentrations.

Limitations to the available data include the inherent design constraints to case reports and retrospective cohort studies, as well as the small numbers of children in some studies. Use of normal-weight historical control subjects for obese children in the context of a pharmacokinetic study is not ideal. Although more information is becoming available, we are still limited in our understanding of pharmacokinetics in obese children. There is no pharmacokinetic information for opioids, benzodiazepines, antibiotics (eg, penicillins, carbapenems), antifungals, cardiac drugs (eg, digoxin, amiodarone), corticosteroids, or anticonvulsants. Limited information is available about drugs that are widely distributed into or can accumulate in adipose tissue. When dosing information is not available for obese children, it may be possible to extrapolate from available adult data, as has been described by Ross et al36 and Burke et al,34 but the effects of the child’s age on pharmacokinetics should be considered.

ACKNOWLEDGMENTS We confirm that all authors have read and approved the manuscript and that there are no other persons who satisfy the authorship criteria that are not listed. We confirm that the order of authors listed in the manuscript has been approved by all of us. The authors received no monetary support for the preparation of this article. Dr. Kendrick wrote the first draft of the manuscript and Dr. Carr wrote the first draft of the abstract. All authors were involved in revising the manuscript.

CONCLUSIONS From the available studies, it seems that TBW is an appropriate size descriptor for dosing antineoplastic agents, succinylcholine, and cefazolin. Obese children seem to require less heparin, enoxaparin, and warfarin per kilogram TBW than normal-weight children; however, providing standard adult doses may be insufficient. Obese children may also require less vancomycin and aminoglycosides per kilogram TBW than normal-weight children. For these medications, an alternate size descriptor in children has not been described, and initial dosing based on TBW and monitoring serum concentrations (vancomycin and aminoglycosides) or coagulation parameters (heparin, enoxaparin, and warfarin) may be appropriate. Obese children require less propofol than normal-weight children; however, there is limited information about dosing other anesthetics or opioids.

1920

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article. The authors have received no support (past or present) from industry or organizations that might have influenced this work.

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Address correspondence to: Jennifer Kendrick, BSc(Pharm), PharmD, Pharmacy Department, Children's and Women's Health Centre of British Columbia, Room OB7, 4500 Oak Street, Vancouver, BC V6H 3N1. E-mail: [email protected]

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