Oral levothyroxine therapy postbariatric surgery: Biopharmaceutical aspects and clinical effects

Surgery for Obesity and Related Diseases 15 (2019) 333–341

Controversies in Bariatric Surgery

Oral levothyroxine therapy postbariatric surgery: Biopharmaceutical aspects and clinical effects Carmil Azran, Pharm.D. a,1, Daniel Porat, M.Sc. b,1, Noa Fine-Shamir, M.Sc. b, Nirvana Hanhan, M.Sc. b, Arik Dahan, Ph.D. b,∗ b Department

a Herzliya Medical Center, Herzliya, Israel of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Received 24 July 2018; received in revised form 13 December 2018; accepted 4 January 2019

Abstract

Background: Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity. Objective: The purpose of this work was to provide a mechanistic overview of levothyroxine absorption, and to thoroughly analyze the expected effects of bariatric surgery on oral levothyroxine therapy. Methods: We performed a systematic review of the relevant literature reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. A PubMed search for relevant keywords resulted in a total of 14 articles reporting levothyroxine status before versus after bariatric surgery. Results: Different mechanisms may support opposing trends as to levothyroxine dose adjustment postsurgery. On the one hand, based on impaired drug solubility/dissolution attributable to higher gastric pH as well as reduced gastric volume, compromised levothyroxine absorption is expected. On the other hand, the great weight loss, and altered set-point of thyroid hormone homeostasis with decreased thyroid-stimulating hormone after the surgery, may result in a decreased dose requirement. Conclusions: For patients after bariatric surgery, close monitoring of both the clinical presentation and plasma thyroid-stimulating hormone and T4 levels is strongly advised. Better understanding and awareness of the science presented in this article may help to avoid preventable complications and provide optimal patient care. (Surg Obes Relat Dis 2019;15:333–341.) © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Key words:

Bariatric surgery; Drug absorption; Levothyroxine; Obesity; Oral drug administration; Thyroid hormone deficiency

Bariatric surgery is the most effective weight loss treatment for patients with obesity and has been reported to result in a substantial, long-term (10-yr), weight loss [1]. Furthermore, morbidity from obesity, including diabetes, ∗ Correspondence: Arik Dahan, Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. E-mail address: [email protected] (A. Dahan). 1 CA and DP contributed equally to this work.

hyperlipidemia, and hypertension, resolved or substantially improved in many patients undergoing bariatric surgery [2–4]. Morbid obesity is also associated with hypothyroidism (∼12% prevalence rate of hypothyroidism was reported among patients with obesity) [5], along with increased probability for utilization of thyroid hormone replacement medications in patients undergoing bariatric surgery [6]. Oral levothyroxine has been the treatment of choice for many years, resolving the signs and symptoms of

https://doi.org/10.1016/j.soard.2019.01.001 1550-7289/© 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

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hypothyroidism in most patients [7]. The initial dose is based on the patient’s weight and adjusted based on serum thyroid levels, T4 and thyroid-stimulating hormone (TSH) [8–10]. Absorption of drugs from the gastrointestinal tract is a complex process influenced by physiologic, physicochemical, and biopharmaceutical factors [11]. Anatomic and physiologic changes after bariatric surgery can lead to absorption changes of many drugs [12–14]. For this reason, plasma levels and clinical outcomes should be carefully monitored in patients before and after bariatric surgery [15,16]. The purpose of this work was to provide an overview of the oral absorption of levothyroxine, a narrow therapeutic index drug [17], and to thoroughly analyze the expected clinical outcomes of oral levothyroxine therapy after bariatric surgery. Better understanding and awareness of the science presented in this article may help to avoid preventable complications, and to provide optimal patient care. The effects of bariatric surgery on oral drug absorption The most common bariatric surgeries today are bypass procedures, such as laparoscopic bypass surgery (e.g., Roux-en-Y gastric bypass [RYGB] and single-anastomosis gastric bypass, or minibypass) and laparoscopic sleeve gastrectomy [18]. Sleeve gastrectomy reduces the volume of the stomach by a longitudinal resection of its greater curvature part. Minibypass and RYGB bypass most of the stomach, duodenum, and upper small intestine, directing the gastric content to the lower small intestine [19]. Another bariatric procedure is the implantation of a ring that constricts the upper part of the stomach. The anatomic and physiologic changes after bariatric surgery (i.e., restriction of the stomach volume and shortening of the small intestine length and transit time) may lead to significant changes in the absorption of drugs and nutrients [13]. While malabsorption of food components is desirable and helps to achieve and maintain weight loss, changes in drug absorption may be problematic. Drug absorption is a multistep process, and each step may be affected by the surgery. Disintegration and deaggregation of the drug product, followed by dissolution of the drug substance, are prerequisites for successful oral drug absorption from an immediate-release product [20]; these processes occur mostly in the stomach, and hence, may be impaired after bariatric surgery. Gastric motility has an important role in disintegration, and may be insufficient due to the reduced volume of the stomach after the surgery (<20% of the healthy stomach) [21]; the small stomach also limits the volume of water ingested with the drug product, and this reduced gastric fluid in the operated stomach may harm drug dissolution.

The remaining small gastric pouch contains far fewer parietal cells than the healthy stomach, leading to significantly higher pH after the surgery. In bypass surgeries (unlike sleeve gastrectomy), the gastrojejunal anastomosis and the lack of effective pyloric sphincter allows the small intestinal and the gastric content to mix, again leading to higher pH after the surgery [22]. In addition, many patients take acid-reducing drugs, antacids, proton pump inhibitors (PPIs), or H2 blockers as prophylaxis against gastroesophageal reflux disease and ulcers, which may further affect gastric pH [23]. Actual measurements of the gastric pH after bariatric surgery are not available in the literature, but pH levels of 6.4 to 6.8 were used in the literature as the postbariatric surgery gastric pH [24,25]. Because the solubility/dissolution of ionizable drugs is pH dependent, bariatric surgery can considerably affect this process. At the normal acidic stomach (pH ∼1), acidic drugs present mostly as unionized molecules, which is the lower solubility form of the drug, while drugs with basic (alkaline) nature are mostly ionized, which makes them freely soluble with complete dissolution under these conditions [26]. The increased/neutral gastric pH after bariatric surgery may change the ionization state of these drugs, and as a result, the solubility of basic drugs may be seriously hampered postsurgery [27,28]. From the stomach, the drug then passes to the small intestine, the main site of drug absorption. Bypassing the upper small intestine (e.g., in RYGB or minibypass procedures) shortens the intestinal transit time, and reduces the effective intestinal surface area available for drug permeation. This limited time and surface area may decrease the probability for completion of drug dissolution and absorption. Bile salts and other biliopancreatic secretions contribute to the solubility of lipophilic drugs, and after RYGB, these secretions become available only in the common channel at the lower part of the small intestine. This may cause impaired dissolution and absorption of lipophilic drugs. After dissolution, passive/active drug permeability into the gut membrane will complete the absorption process. The limited small intestinal transit time and surface area after RYGB surgery may decrease the fraction of drug dose permeating the gut wall. Active drug permeability may be significantly affected by bypass surgery; the expression of some transporters along the small intestine is asymmetric, and bypassing the upper intestinal segments may alter the overall drug transport. For instance, the expression of the efflux transporter P-glycoprotein (P-gp) increases aborally, while multidrug resistance-associated protein 2 (MRP2) follows the opposite trend [29–31]. Similarly, the expression of metabolic enzymes within the epithelial cells (e.g., cytochrome P450 3A4) decreases aborally, and bypassing the upper intestinal regions that are cytochrome P450 3A4 rich may increase the fraction of drug dose escaping intestinal metabolism, resulting in

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higher drug blood levels after RYGB. Atorvastatin is one example for this phenomenon in some patients [32,33]. Biopharmaceutics of levothyroxine The many factors concomitantly influencing oral drug absorption make this process complex and intriguing. Yet, the seminal work by Amidon et al. [34] has identified the following 2 fundamental key parameters controlling oral drug absorption: the solubility/dissolution of the drug dose in the aqueous gastrointestinal milieu, and the permeability of the drug through the gut membrane [34]. Based on whether the solubility and the permeability are high or low, drugs are classified into 1 of 4 categories of the biopharmaceutics classification system (BCS). For drugs that exhibit both high solubility and high permeability, complete absorption may be expected [35]. On the other hand, when both these key parameters are low (i.e., BCS class 4), the compound is generally considered a poor oral drug candidate [36]. In the following section, levothyroxine solubility and permeability characteristics will be analyzed. Determination of levothyroxine solubility According to the U.S. Food and Drug Administration, European Medicines Agency, and World Health Organization definitions, a drug substance is considered “highly soluble” when the highest dose strength is soluble in 250 mL, over a pH range of 1 to 6.8 at 37°C. The 250-mL volume is based on typical bioequivalence study protocols that administer the drug product to fasting volunteers with a glass (∼8 oz) of water. Experimental solubility data of levothyroxine sodium was published by Won et al. [37]; a solubility decrease over the physiologically relevant pH range of 1 to 6 was reported, with 10 μg/mL at pH 1, and approximately 0.25 μg/mL at the pH range of 3 to 6 (Fig. 1). This solubility pattern is in line with the drug’s alkaline amine group. The classification of levothyroxine as either high- or low-solubility compound would depend on whether the highest dose is solubilized in 250 mL. For a dose of 200 μg, complete solubility is expected at pH approximately 1, whereas at any higher pH, levothyroxine is clearly a low-solubility drug. The pH of the healthy stomach increases from pH of approximately 1 in the fasted state, to neutral pH after a meal; this explains the instruction for patients to take levothyroxine on an empty stomach, and not eat for at least half an hour after drug ingestion [38]. Overall, levothyroxine can be unequivocally classified as a low-solubility compound. Determination of levothyroxine permeability A drug substance is considered highly permeable when the measured extent of absorption is >85%, based on sys-

Fig. 1. Experimental pH-dependent solubility of levothyroxine sodium. Reproduced with permission from Pharmaceutical Research [37].

temic bioavailability or mass balance studies. Levothyroxine is a lipophilic drug with log P of 3.5 [39]. However, it has poor intestinal permeability due to the molecule’s zwitter-ionic polar side chain, which prevents its penetration through the membrane’s lipid bilayer [40]. The drug’s low permeability contributes to variable absorption and bioavailability [41]. According to the above data of solubility and permeability, the most appropriate BCS classification for levothyroxine is class 4.

Levothyroxine therapy postbariatric surgery Levothyroxine is absorbed mostly from the jejunum and the upper ileum [42]; bariatric surgery, and particularly bypass surgery, causes anatomic and physiologic changes in the upper small intestine, so absorption changes of the drug may be expected postsurgery. As mentioned above, low gastric pH of approximately 1 is favorable for levothyroxine successful dissolution, and after bariatric surgery, gastric pH is significantly increased. In addition, many patients are prescribed PPIs\H2 blockers postsurgery that further contribute to the elevated gastric pH. Indeed, decreased response to levothyroxine in patients taking the drug with PPIs\food has been reported before [43–45]. Additionally, patients are instructed to take vitamins and mineral supplements after the surgery. However, a decrease in levothyroxine absorption has been reported when administrated concomitantly with vitamins/minerals, such as calcium carbonate, ferrous sulfate, and aluminum hydroxide, by adsorption to levothyroxine and formation of insoluble complexes [38,46–48]. All of these mechanisms indicate the potential for impaired levothyroxine absorption after bariatric surgery.

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Based on the above, we performed a systematic review of the relevant literature, reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. PubMed was searched for the following keyword combinations: “bariatric levothyroxine”, “bariatric replacement thyroid”, “weight bypass levothyroxine”, “weight bypass replacement thyroid”, “sleeve levothyroxine”, and “sleeve replacement thyroid”. As of December 2018, 116 results were obtained. After excluding duplications, irrelevant articles, review articles, and papers that reported unchanged levothyroxine requirements after surgery, there was a total of 14 papers, 12 reporting postoperative changes in levothyroxine requirements and 2 pharmacokinetic studies of the drug before versus after bariatric surgery. Not many high-quality, large, prospective studies are available, looking into the effects of bariatric surgery on levothyroxine and hypothyroidism (Table 1). Although some studies reported that higher dose requirement of many drugs may be needed after bariatric surgery [13,49], other studies of levothyroxine show opposite results. In those studies, the loss of both fat and lean body mass results in decreased postoperative levothyroxine requirement, as its dose also depends on the patient’s weight. Fierabracci et al. [50] evaluated 93 patients with obesity approximately 2 years postsurgery and found significant reduction in levothyroxine dose in 47 patients, proportional to the reduction in lean body mass. They concluded that after reaching a steady weight postsurgery, a dose of 1.4 μg/kg was sufficient for most patients. Chikunguwo et al. [51] found that before bariatric surgery 10.5% of patients had subclinical hypothyroidism, which resolved in all of them 6 to 12 months postsurgery. The effect of bariatric surgery on levothyroxine requirements and on thyroid function tests was recently studied. Results differ with most studies showing improved thyroid function tests with a decrease in TSH leading to dose reduction. In a recent study by Neves et al. [52], 949 patients who had either normal or high TSH were followed for 12 months, and it was found that TSH was decreased postsurgery without further interventions [52]. Zendel et al. [53] looked at patients after sleeve gastrectomy and RYGB and found that mean TSH postsurgery significantly decreased and dose requirements were lower. In a recent retrospective study by Pedro et al. [54], levothyroxine dose requirements were compared before and after bariatric surgery. It was found that most patients did not need dose adjustment, and drug requirements did not differ between malabsorptive and restrictive procedures [54]. An altered set point of thyroid hormone homeostasis may also contribute to the decreased levothyroxine dose needed after the surgery [55]. Leptin regulates hypothalamic thyrotropin releasing hormone gene expression. Leptin is found in higher levels in people with obesity, leading to

an increased serum TSH levels. Elevated plasma bile acid levels in patients who previously had RYGB surgery is another possible explanation of the change in the set point. Bile salts have an important role in activation of TGR-5 receptor, leading to increased activity of type 2 deiodinase, which converts T4 to active T3 and subsequently decreased TSH levels [56,57]. However, results are not consistent with all studies; in early cases, Azizi et al. [58] and Bevan et al. [59] described increased requirements of levothyroxine after jejunoileal bypass surgeries. In a recent case report, resistance to levothyroxine was described although high doses were used. Improvement was demonstrated when a liquid formulation was administered [60,61]. This was not the first case describing this phenomenon, as a case series published by Pirola et al. [62] also demonstrated that, in 4 RYGB patients, TSH levels postsurgery failed to be balanced by solid dosage form, and switching to liquid levothyroxine formulation managed to normalize the high TSH levels. Even 17 months postsurgery, switching back to the tablet form was not successful. Although this advantage of liquid formulation may be attributable to the change in disintegration/dissolution and the faster gastric emptying postsurgery, a study of 152 unoperated patients with no gastric disorders who were switched to liquid levothyroxine formulation showed better control of TSH levels [63]. This may be the reflection of levothyroxine low-solubility and -permeability characteristics, which lead to high variability that can be reduced when using liquid dosage form. Discussion Levothyroxine is a low-permeability, low-solubility BCS class 4 drug, and thus, it is very susceptible to changes in the gastrointestinal milieu after bariatric surgery. Levothyroxine is also a narrow therapeutic index drug, hence small changes in levothyroxine exposure could result in abnormal TSH levels with significant clinical consequences [64,65]. For these reasons, levothyroxine dose adjustment after bariatric surgery is extremely important, yet, difficult to predict. On the one hand, based on impaired drug solubility/ dissolution attributable to higher gastric pH and reduced gastric volume, as well as co-administration of levothyroxine with food or other drugs and vitamins/minerals supplements, impaired absorption of levothyroxine is expected. On the other hand, the great loss of weight after the surgery and an altered set point of thyroid hormone homeostasis may result in a decreased dose requirement. Apparently, dose reduction is needed for most patients, as a growing body of evidence shows that the majority of patients undergoing modern bariatric surgeries demonstrated decreased levothyroxine dose requirements after the

Table 1 Summary of literature reports of changes in levothyroxine therapy after bariatric surgery. Type of BS

Time after N patients Thyroid status Lt4 dosage pre- and BS, mo presurgery postsurgery, μg/d

P value Lt4 change

TSH levels preand postsurgery, μU/mL

P value TSH change

Conclusion

Ref

Retrospective

RYGB, 58%, AGB, 33%, SG, 9% RYGB, 81%, AGB, 19% RYGB, 58%, AGB, 21%, SG, 21%

28

93

Hypothyroid

130.6 → 116.2

<.001

1.56 → .84

<.001

[50]

Euthyroid

0

N/A

4.5 → 1.9

<.001

718

Normal TSH

0

N/A

1.57 → 1.53

.063

No need for Lt4 dose adjustments, but TSH should be periodically monitored PostBS weight loss may resolve subclinical hypothyroidism Significant decrease of TSH levels 12 mo after BS, and the decrease is significantly greater in patients with baseline high-normal TSH levels

6, 12

86

12

Case report Case report Case reports

RYGB, 61%, AGB, 20%, SG, 19% SG, 83%, RYGB, 17% RYGB, 61%, SG, 26%, AGB, 12% JIB JIB RYGB

12

231

High-normal TSH

0

N/A

3.23 → 2.38

<.001

6, 12

93

Hypothyroid

98.4 → 89.7

<.02

3.9 → 3

<.05

12

57

Hypothyroid

100 → 100

.07

1.77 → 1.31

N/A

28 48 12

1 1 4

Hypothyroid Euthyroid Hypothyroid

200 → 600 0 → 600 175 → 175

N/A N/A N/A

N/A N/A N/A

JIB

26

1

Hypothyroid

200 → 800

N/A

1.8 → 36 N/A → 48 3.7 → 1.6 (liquid), 23.6 (tablet) N/A → 80

Case report

N/A

PK

RYGB

2–3

30

Thyroid nodular disease

N/A

N/A

3.56 → 2.52

.016

Retrospective

SG

36

19

Hypothyroid

111.8 → 75.6

N/A

N/A → .3

N/A

PK PK PK

BPD SG RYGB

1 1 1

15 10 7

Euthyroid Euthyroid Euthyroid

N/A N/A N/A

N/A N/A N/A

2.57 → 3.07 2.56 → 2.37 1.88 → 2.02

>.05 >.05 >.05

Prospective

SG, 68%, RYGB, 32%

>12

90

Hypothyroid

114 → 85

N/A

4.2 → 2.3

<.01

Retrospective Retrospective

Retrospective

Prospective Retrospective

[51] [52]

Improved thyroid function and reduced [53] medication dosages BS type was not predictive of Lt4 dose [54] changes Lt4 dose/kg increased at 1 yr Periodic thyroid status assessments [58] Larger dose expected in these patients [59] A liquid formulation may benefit [62] patients with impaired Lt4 absorption Serious impairment of thyroid hormone [66] absorption PK parameters: maximum TT4, and [67] AUC of both TT4 and FT4 were significantly higher after RYGB. Significant delay in Lt4 absorption after RYGB SG results in reduced Lt4 requirement [68] in most patients with clinical hypothyroidism Lt4 absorption (AUC and Cmax ) [69] increase after SG and BPD. Stomach and duodenum are not sites for Lt4 absorption Clinical improvement with reduction [70] and even cessation of Lt4 usage. More patients in SG group did not require Lt4 after surgery

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Study design

(continued on next page) 337

338

Study design

Type of BS

Time after N patients Thyroid status Lt4 dosage pre- and BS, mo presurgery postsurgery, μg/d

Prospective

RYGB

17

23

Hypothyroid

Retrospective

SG

6

3

Prospective

RYGB

3–8

13

Hypothyroid 181 → 166.7 (pituitary insufficiency) Hypothyroid N/A

Prospective

BPD

3–8

4

Hypothyroid

N/A

N/A

Case report

SG

N/A

1

Hypothyroid

175 → 1000 (tablet), 125 (liquid)

N/A

123.5 → 101.1

P value Lt4 change

TSH levels preand postsurgery, μU/mL

P value TSH change

Conclusion

Ref

N/A

N/A

N/A

[71]

N/A

N/A

N/A

N/A

2.2 → 7.6 (tablet), 3.8 (liquid) 2.6 → 8.8 (tablet), 3.1 (liquid) N/A → 254

<.001

Reduction of Lt4 requirements is likely a result of BMI decrease. Postoperative thyroid function improvement is more likely in older patients. SG does not impair hormone replacement therapy absorption in patients with hypothalamic obesity Liquid Lt4 could overcome Lt4 malabsorption after RYGB/BPD.

BS results in Lt4 malabsorption by different mechanisms, which can be partly overcome by liquid formulation

[74]

[72]

[73]

<.01 N/A

BS = bariatric surgery; Lt4 = Levothyroxine; TSH = thyroid-stimulating hormone; RYGB = Roux-en-Y gastric bypass; AGB = adjustable gastric banding; SG = sleeve gastrectomy; N/A = not applicable; JIB = jejunoileal bypass; PK = pharmacokinetic; TT4 = change in total T4; AUC = area under the curve; FT4 = change in free T4; BPD = biliopancreatic diversion; Cmax = maximal Lt4 plasma concentration; BMI = body mass index.

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Table 1 (continued)

Carmil Azran, Daniel Porat and Noa Fine-Shamir et al. / Surgery for Obesity and Related Diseases 15 (2019) 333–341

surgery [50,55]. However, meta-analysis and large prospective studies, looking at changes to thyroid function and thyroid supplement requirements after bariatric surgery are needed. Meanwhile, and until conclusive evidence is available, guidance to bariatric surgery patients about levothyroxine administration should include the following: (1) as in all patients, take the drug on an empty stomach, at least 30 minutes before meal; (2) take levothyroxine 4 hours apart from medications that interfere with absorption, such as PPIs\H2 blockers and vitamins/minerals supplements that are frequently prescribed postsurgery; (3) perform regular thyroid function tests starting with 6 weeks postsurgery and then every 3 months until steady state is achieved; and (4) take crushed or liquid levothyroxine for at least 2 months [13,62]. For patients in whom TSH increases after the surgery, increasing the time that levothyroxine is given in a crushed/liquid form may be beneficial. To summarize, careful monitoring of thyroid laboratory measures, such as serum TSH, T3, and T4 levels, is necessary before and after bariatric surgery to determine the appropriate postoperative levothyroxine dose. Further studies are required to evaluate the influence of bariatric surgery on the absorption of thyroid replacement therapy and to provide guidance to clinicians on the potential effects of the different bariatric procedures.

Conclusions In conclusion, given the many potentially altered parameters affecting the absorption of levothyroxine after bariatric surgery, and although most studies looking at thyroid function and levothyroxine after bariatric surgery show a trend toward decrease in TSH, there is contradicting evidence regarding postoperative oral levothyroxine dose requirement. Also, clinical monitoring as well as and monitoring of TSH and T4 levels should be routinely performed and levothyroxine dose should be adjusted accordingly. It is of great importance that high-quality studies looking at the effects of the different types of surgery are performed to guide clinicians in the management of this highly prevalent condition in the bariatric population.

Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.

Supplementary material Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.soard. 2019.01.001.

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