Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring

Journal of Cystic Fibrosis 12 (2013) 403 – 406 www.elsevier.com/locate/jcf

Short Communication

Timing of inhaled tobramycin affects assessment of intravenous tobramycin pharmacokinetic monitoring Antine E. Stenbit a,⁎, Wendy M. Bullington b , Julie L. Heh b , Patrick A. Flume a

a, c

Department of Medicine, Division of Pulmonary and Critical Care, Medical University of South Carolina, Charleston, SC 29425, United States b Department of Clinical Pharmacy Services, Medical University of South Carolina, Charleston, SC 29425, United States c Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States Received 6 July 2012; received in revised form 15 November 2012; accepted 16 November 2012 Available online 20 December 2012

Abstract Background: Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. Methods: Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5–9 h after the IV dose. Results: Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin. Conclusion: Trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing. © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Tobramycin levels; Inhaled tobramycin; TOBI

1. Introduction The Cystic Fibrosis Foundation (CFF) Pulmonary Guidelines recommend tobramycin inhalation solution (TIS) for suppression of chronic airway infection to improve lung function and reduce the frequency of pulmonary exacerbations [1]. Nonetheless, patients still experience acute exacerbations of lung infection. Antibiotics are commonly used in the treatment of pulmonary exacerbations and often include an aminoglycoside such as tobramycin [2]. The CFF Pulmonary Guidelines [2] recommended continuing chronic therapies for maintenance of lung health during treatment of an acute exacerbation of pulmonary disease, but made no recommendation on whether to continue TIS when using intravenous (IV) tobramycin [2]. ⁎ Corresponding author at: 96 Jonathan Lucas St, Clinical Science Building Suite 812, Charleston, SC 29425, United States. Department of Clinical Pharmacy Services, 150 Ashley Avenue, PO Box 250584, Charleston, SC 29425, United States. Tel.: +1 843 792 9219, +1 843 792 2665; fax: +1 843 792 0732, +1 843 792 0566. E-mail address: [email protected] (A.E. Stenbit).

Since inhaled tobramycin is absorbed systemically, albeit in low concentrations and with great variation [3–5], there remains the potential that it could influence interpretation of serum tobramycin pharmacokinetic (PK) monitoring [6–8]. Computer-assisted PK modeling, using published PK parameters associated with TIS, predicted that the timing of the inhaled dose, particularly if given in the latter portion of the IV dosing interval, may complicate the assessment of traditional PK parameters used to adjust IV dosing. We evaluated the significance of inhaled tobramycin on serum concentrations and the calculated elimination rate constant in patients concomitantly treated with parenteral tobramycin. 2. Methods This single center study was conducted at the Medical University of South Carolina (MUSC) and approved by the Institutional Review Board. Adult CF patients infected with Pseudomonas aeruginosa and admitted to the hospital for treatment of a pulmonary exacerbation were eligible for

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A.E. Stenbit et al. / Journal of Cystic Fibrosis 12 (2013) 403–406

Fig. 1. Graphical representation of interventions. The open arrows represent the times that the IV tobramycin was given every 12 h (Q12h) on Day 1 and Day 2. The smaller arrows are the times at which the serum was collected. The first dose of IV tobramycin was considered time 0 each day. The TIS was given between 5 and 9 h after the third dose (morning dose on Day 2).

participation. Treatment of CF exacerbations at our center includes the use of twice daily dosing of IV tobramycin (Cmax goal 15–17 μg/mL). 2.1. Study design Patients continued all chronic medications with the exception that TIS was held at the time of admission. The appropriate dosing during a previous exacerbation determined the IV tobramycin dose. The study procedures began the day after admission and the design is shown in Fig. 1. Tobramycin PK parameters were calculated both without (Day 1) and with (Day 2) TIS 300 mg given 5–9 h after the morning dose of IV tobramycin, which was at the same time on Days 1 and 2. PK parameters were calculated from tobramycin levels drawn at

2 and 11 h after the administration of the morning dose. Serum tobramycin concentrations were measured by a standard chemiluminescence assay (ADVIA Centaur® Tobramycin, Siemens). Safety laboratories included serum creatinine. Concentration minimum (Cmin), concentration maximum (Cmax) and elimination rate constant (ke) were calculated using standard PK equations. 2.2. Statistics The absorption of inhaled tobramycin is highly variable. Following the standard dose, mean (and median) peak concentration is approximately 1 μg/mL with a reported range of 0.18–3.62 μg/mL [3]. We predicted that a measurable effect would be seen in 50% of patients, but would be clinically

Table 1 Patient demographics and pharmacokinetic data. The demographics of the patients enrolled in the study are described in this table. Included are sex, age, FEV1 percent predicted, BMI (kg/m2), creatinine (mg/dL), tobramycin (IV) dose (mg). The Cmin and ke for each patient on Day 1 and Day 2 are reported in the far right columns. The Cmin is reported in μg/mL and ke in h−1. The final column shows if the patient has been diagnosed with cystic fibrosis related diabetes. Patient

Age

Sex

FEV1 (%predicted)

BMI (kg/m2)

Creatinine (mg/dL)

Tobramycin dose (mg)

Cmin (μg/mL) Day 1

Cmin (μg/mL) Day 2

Ke (h−1) Day 1

Ke (h−1) Day 2

CFRD

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

28 30 22 30 28 18 18 22 25 31 31 28 22 21 27 22 28 18 18 24

F F F F M M F F M F F F M M M F M F F M

49 46 60 45 53 37 65 38 66 53 30 70 54 41 63 85 45 52 60 26

25.1 19.6 20.1 20.3 18.8 17.2 26.1 19.8 22.0 17.1 16.8 20.9 17.9 23.8 21.8 20.8 21.4 22.4 21.8 22.4

0.7 0.7 0.7 0.9 0.9 0.8 0.6 0.8 1.1 0.6 0.5 0.6 0.8 0.9 1.2 0.6 0.8 0.5 0.9 0.9

315 260 300 250 280 290 320 260 200 440 250 300 250 350 350 225 350 275 250 375

0.4 1.4 0.22 1.4 0.78 0.66 0.82 0.35 0.5 0.33 0.44 0.3 0.3 0.43 1.9 0.8 1 0.29 0.7 1

3 2.3 0.11 0.95 0.76 0.28 2.1 0.21 0.95 0.6 0.44 1.2 1.3 1.8 1.4 1.1 0.2 0.8 1 1.9

0.302 0.275 0.41 0.168 0.271 0.299 0.329 0.344 0.29 0.41 0.272 0.404 0.369 0.386 0.16 0.25 0.2 0.41 0.302 0.18

0.188 0.171 0.506 0.257 0.243 0.295 0.158 0.324 0.235 0.293 0.273 0.245 0.167 0.13 0.218 0.25 0.2 0.29 0.25 0.2

No No Yes Yes Yes No No Yes Yes Yes No Yes Yes Yes No No No No Yes No

A.E. Stenbit et al. / Journal of Cystic Fibrosis 12 (2013) 403–406

significant in fewer. Since this is a proof-of-concept study, we chose a sample size of 20 subjects based on the estimate that we would find a clinically significant finding in 10–15% of patients. 3. Results The demographics of the patients enrolled in the current study are in Table 1. All patients were pancreatic insufficient and had a sputum culture that grew P. aeruginosa in the previous 6 months. The average IV tobramycin dose was 295 mg (range 200–440 mg), an average of 5 mg/kg/dose (range 4.7 to 10.5 mg/kg/dose). Concomitant medications that may affect the clearance of tobramycin by altering renal function were vancomycin (6 patients) and sulfamethoxazole/ trimethoprim (3 patients). All patients had normal renal function. Nine had previously been diagnosed with cystic fibrosis related diabetes (CFRD). PK data are shown in Fig. 1 and Table 1. Baseline PK data demonstrated only 3 patients with Cmin N 1 μg/mL and no patient had a Cmin N 2 μg/mL (Fig. 2A). However, there were

A

B

Fig. 2. Minimum concentration (trough) and elimination rate constant over time of serum tobramycin. A: minimum concentration (trough) of serum tobramycin. The minimum concentration (Cmin) was calculated for each patient on Day 1 and again on Day 2. The graph represents a line for each patient drawn from the Cmin calculated on Day 1 to the Cmin calculated on Day 2. Solid black lines indicate patients whose Cmin increased on Day 2 when compared to Day 1. For our center, if the Cmin is over 1 μg/mL, the patient's interval of IV tobramycin will be increased to achieve a Cmin b1 μg/mL. The broken black line indicates a Cmin of b 1 μg/mL. B: elimination rate constant over time. This graph represents a line drawn from the elimination rate constant (ke) calculated on Day 1 (no TIS) to the ke calculated on Day 2 (after TIS) for each patient. Dotted lines indicate patients whose ke decreased on Day 2 when compared to Day 1.

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notable changes following the dose of TIS. Twelve patients (60%) had an increase in Cmin. Of those, there were now 9 patients (45%) with a Cmin ≥ 1 μg/mL and 3 (15%) with a Cmin N 2 μg/mL. Seven (35%) of the patients had a doubling of their Cmin following the dose of TIS. Six of the 9 patients with an increase in Cmin to ≥ 1 μg/mL were females. There were no other distinguishing characteristics in the demographics such as creatinine, chronic TIS therapy, other colonizing bacteria, nutritional status, CFRD status, time of administration of TIS in the dosing range (5 to 9 h) or lung impairment. The ke at baseline ranged between 0.16 and 0.41 h − 1; this range following TIS on Day 2 was 0.13 to 0.51 h − 1 (Fig. 2B). Fourteen (70%) of the patients had a ke decrease on Day 2 when compared to Day 1 (baseline).

4. Discussion We confirmed previous findings that there is systemic absorption of inhaled tobramycin [3,5]. Although initial studies conducted with TIS suggested that the systemic absorption of TIS was not clinically significant, these studies were conducted in patients on chronic treatment with TIS and did not report measures in patients also receiving intravenous dosing. Here we have demonstrated that concomitant use of inhaled tobramycin during an acute exacerbation, when given in the latter portion of the dosing interval of intravenous tobramycin, can result in measurable effects on serum PK monitoring of the drug. There are two case reports of tobramycin concentrations measured in patients on concomitant IV and inhaled tobramycin [9,10]. Both of these studies showed that there was an increase in the concentration of tobramycin measured by fingerprick blood sampling, but it was attributed to contamination of the sampling area with tobramycin after TIS. In our study, the samples were obtained by venipuncture or from a central venous catheter and the sampling area was cleaned thoroughly with chlorhexidine prior to the sample being drawn, eliminating this possibility. It is important to note that our findings do not offer insights into questions of efficacy or toxicity. We did not find any concerns for safety, but we were measuring drug concentrations after only one dose of TIS. Any studies to assess efficacy or safety would have to take timing of the inhaled drug into consideration. Of key importance is that should one choose to use TIS concomitantly with IV tobramycin, knowledge of the timing of TIS is relevant to standard monitoring of tobramycin concentrations. For example, an elevated trough concentration might be perceived that the patient is not clearing the drug sufficiently, when it might actually be the result of absorption of TIS given late in the dosing interval. This could result in a change in the IV dosing regimen, either by reducing the dose or by increasing the dosing interval. Both methods would reduce the overall tobramycin exposure, and may result in a relative undertreatment of the infection given the concentration dependent killing effect of the aminoglycoside [11].

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In conclusion, trough tobramycin concentrations were significantly influenced in some CF patients (45%) following TIS when given in the latter part of the IV dosing interval, consistent with significant absorption of inhaled drug. To avoid undue influence of TIS on PK monitoring of IV tobramycin, it would be recommended that when the two are given concomitantly that TIS is given in the first half of the IV dosing interval. This study does not imply that TIS is unsafe when given concomitantly with IV tobramycin, but does suggest that it can influence interpretation of PK monitoring during treatment of a pulmonary exacerbation. Acknowledgments We would like to acknowledge John Bosso Pharm D, Wayne Barfield RRT, Mary Lester RRT, and the nurses on 8E and 8W at MUSC for their assistance. This study was made possible by a grant from the Novartis Pharmaceuticals Corporation. The Novartis Corporation reviewed the manuscript, but did not have a role in the collection, interpretation, presentation of the data, or the writing of the manuscript. References [1] Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel Jr PJ, Willey-Courand DB, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176(10):957–69 [Epub 2007/09/01]. [2] Flume PA, Mogayzel Jr PJ, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009;180(9):802–8 [Epub 2009/09/05].

[3] Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest 2002;122(1):219–26 [Epub 2002/07/13]. [4] Geller DE, Rosenfeld M, Waltz DA, Wilmott RW. Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system. Chest 2003;123(1): 28–36 [Epub 2003/01/16]. [5] Touw DJ, Jacobs FA, Brimicombe RW, Heijerman HG, Bakker W, Briemer DD. Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis. Antimicrob Agents Chemother 1997;41(1):184–7 [Epub 1997/01/01]. [6] McRorie TI, Bosso J, Randolph L. Aminoglycoside ototoxicity in cystic fibrosis: evaluation by high-frequency audiometry. Am J Dis Child 1989;143(11):1328–32. [7] Mingeot-Leclercq M-P, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999;43(5):1003–12. [8] Scott CS, Retsch-Bogart GZ, Henry MM. Renal failure and vestibular toxicity in an adolescent with cystic fibrosis receiving gentamicin and standard-dose ibuprofen. Pediatr Pulmonol 2001;31(4):314–6 [Epub 2001/04/05]. [9] Elidemir O, Maciejewski SR, Oermann CM, et al. Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin. Pediatr Pulmonol 2000;29(1):43–5 [Epub 1999/12/29]. [10] Redmann S, Wainwright C, Stacey S, Champion A, Mitchell P, Cheney J, et al. Misleading high tobramycin plasma concentrations can be caused by skin contamination of fingerprick blood following inhalation of nebulized tobramycin (TOBI): a short report. Ther Drug Monit 2005;27(2):205–7 [Epub 2005/03/30]. [11] MacArthur RD, Lolans V, Zar FA, Jackson GG. Biphasic, concentrationdependent and rate-limited, concentration-independent bacterial killing by an aminoglycoside antibiotic. J Infect Dis 1984;150(5):778–9 [Epub 1984/11/01].