New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 7909660 Publication Model: Print Cited Medium: Internet ISSN: 1536-3694 (Electronic) Linking ISSN: 01634356 NLM ISO Abbreviation: Ther Drug Monit Subsets: MEDLINE

Publication: Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: [New York] Raven Press.

Tobramycin* ; Cystic Fibrosis*/drug therapy ; Cystic Fibrosis*/complications; Humans ; Adult ; Aged ; Retrospective Studies ; Anti-Bacterial Agents ; Area Under Curve

Background: Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a reevaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations.
Methods: This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (C max ) to the minimal inhibitory concentration (MIC) (C max /MIC ≥8 and ≥10) and area under the curve (AUC) to the MIC (AUC/MIC ≥70 and ≥100) were evaluated.
Results: Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function. According to simulations, doses between 3.4 mg/cm and 4.4 mg/cm were necessary to achieve C max /MIC values of ≥8 and ≥10, respectively. However, higher doses were required to achieve the AUC/MIC targets.
Conclusions: This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with a median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.
Competing Interests: The authors declare no conflict of interest.
(Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Elborn JS. Cystic fibrosis. Lancet. 2016;388:2519–2531.
Lubamba B, Dhooghe B, Noel S, et al. Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clin Biochem. 2012;45:1132–1144.
Stenbit AE, Flume PA. Pulmonary exacerbations in cystic fibrosis. Curr Opin Pulm Med. 2011;17:442–447.
Akkerman-Nijland AM, Akkerman OW, Grasmeijer F, et al. The pharmacokinetics of antibiotics in cystic fibrosis. Expert Opin Drug Metab Toxicol. 2021;17:53–68.
Pang Z, Raudonis R, Glick BR, et al. Antibiotic resistance in Pseudomonas aeruginosa : mechanisms and alternative therapeutic strategies. Biotechnol Adv. 2019;37:177–192.
Drusano GL, Bonomo RA, Bahniuk N, et al. Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa . Antimicrob Agents Chemother. 2012;56:231–242.
Flume PA, Mogayzel PJ, Robinson KA, et al. Clinical practice guidelines for pulmonary therapies committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180:802–808.
Prescott WA Jr. A survey of extended-interval aminoglycoside dosing practices in United States adult cystic fibrosis programs. Respir Care. 2014;59:1353–1359.
Vandenbussche HL, Homnick DN. Evaluation of serum concentrations achieved with an empiric once-daily tobramycin dosage regimen in children and adults with cystic fibrosis. J Pediatr Pharmacol Ther. 2012;17:67–77.
Touw DJ, Knox AJ, Smyth A. Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis. J Cyst Fibros. 2007;6:327–333.
Le T, Lord L, Pignataro S, et al. Evaluating the impact of education on pharmacist tobramycin dose recommendations for cystic fibrosis and a review of perceptions on pharmacist-led charting. J Pharm Pract. 2021:0971900211018419.
Zobell JT, Epps K, Kittell F, et al. Tobramycin and beta-lactam antibiotic use in cystic fibrosis exacerbations: a pharmacist approach. J Pediatr Pharmacol Ther. 2016;21:239–246.
Ochs MA, Dillman NO, Caverly LJ, et al. Aminoglycoside dosing and monitoring for Pseudomonas aeruginosa during acute pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2021;56:3634–3643.
Landmesser KB, Autry EB, Gardner BM, et al. Comparison of the predictive value of area under the curve versus maximum serum concentration of intravenous tobramycin in cystic fibrosis patients treated for an acute pulmonary exacerbation. Pediatr Pulmonol. 2021;56:3209–3216.
Crass RL, Pai MP. Optimizing estimated glomerular filtration rate to support adult to pediatric pharmacokinetic bridging studies in patients with cystic fibrosis. Clin Pharmacokinet. 2019;58:1323–1332.
Alghanem S, Paterson I, Touw DJ, et al. Influence of multiple courses of therapy on aminoglycoside clearance in adult patients with cystic fibrosis. J Antimicrob Chemother. 2013;68:1338–1347.
Hennig S, Standing JF, Staatz CE, et al. Population pharmacokinetics of tobramycin in patients with and without cystic fibrosis. Clin Pharmacokinet. 2013;52:289–301.
Alghanem SS, Touw DJ, Thomson AH. Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis. J Antimicrob Chemother. 2019;74:2311–2317.
Dong M, Rodriguez AV, Blankenship CA, et al. Pharmacokinetic modelling to predict risk of ototoxicity with intravenous tobramycin treatment in cystic fibrosis. J Antimicrob Chemother. 2021;76:2923–2931.
Drennan PG, Thoma Y, Barry L, et al. Bayesian forecasting for intravenous tobramycin dosing in adults with cystic fibrosis using one versus two serum concentrations in a dosing interval. Ther Drug Monit. 2021;43:505–511.
Thirion DJG, Koloskoff K, Caissy JA, et al. Assessment of tobramycin dosing in cystic fibrosis patients with acute pulmonary exacerbation. Poster (356) presented at: North American Cystic Fibrosis Conference; Oct 21-23, 2020; Online.
Nahler G. Dictionary of Pharmaceutical Medicine. Vienna: Springer; 2009:107. Lorentz-formula.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.
Beal S, Boeckmann L, Bauer R, et al. NONMEM user's guides. In: Icon Development Solutions, Ellicott Cit. ISBN 65385267. Corpus ID; 1989–20092009.
Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504.
Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed. 2008;90:154–166.
Aminoglycoside Dosing in Adults. Department of Health, State of Queensland (Queensland Health). Available at: https://www.health.qld.gov.au/__data/assets/pdf_file/0019/713323/aminoglycoside-guidelines.pdf . Accessed June 5, 2022.
Weinstein MP, LewisII JS, Bobenchik AM, et al., eds Performance Standards for Antimicrobial Susceptibility Testing. 30th ed. Wayne, Pennsylvania, USA: Clinical and Laboratory Standards Institute; 2020.
Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 10.0. European Committee on Antimicrobial Susceptibility Testing. Available at: http://www.eucast.org . Accessed June 5, 2022.
Aminimanizani A, Beringer PM, Kang J, et al. Distribution and elimination of tobramycin administered in single or multiple daily doses in adult patients with cystic fibrosis. J Antimicrob Chemother. 2002;50:553–559.
Burkhardt O, Lehmann C, Madabushi R, et al. Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?. J Antimicrob Chemother. 2006;58:822–829.
Aarons L, Vozeh S, Wenk M, et al. Population pharmacokinetics of tobramycin. Br. J Clin Pharmacol. 1989;28:305–314.
Soulsby N, Greville H, Coulthard K, et al. Renal dysfunction in cystic fibrosis: is there cause for concern? Pediatr Pulmonol. 2009;44:947–953.
Smyth A, Tan KHV, Hyman-Taylor P, et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial. Lancet. 2005;365:573–578.
Butterfield JM, Lodise TP, Beegle S, et al. Pharmacokinetics and pharmacodynamics of once-daily administration of intravenous tobramycin in adult patients with cystic fibrosis hospitalized for an acute pulmonary exacerbation. Antimicrob Agents Chemother. 2013;57:5175–5177.
Staubes BA, Metzger NL, Walker SD, et al. Evaluation of a once/day tobramycin Regimen to achieve target concentrations in adult patients with cystic fibrosis. Pharmacotherapy. 2016;36:623–630.
Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43:1549–1555.
Paquette F, Bernier-Jean A, Brunette V, et al. Acute kidney injury and renal recovery with the use of aminoglycosides: a large retrospective study. Nephron. 2015;131:153–160.
Mouton JW, Jacobs N, Tiddens H, et al. Pharmacodynamics of tobramycin in patients with cystic fibrosis. Diagn Microbiol Infect Dis. 2005;52:123–127.
Smith PF, Ballow CH, Booker BM, et al. Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients. Clin Ther. 2001;23:1231–1244.
Coulthard KP, Peckham DG, Conway SP, et al. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis—caution with trough concentrations. J Cyst Fibros. 2007;6:125–130.
Praet A, Bourguignon L, Vetele F, et al. Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis. Antimicrob Agents Chemother. 2021;65:e0073721.
Smyth A, Tan KHV, Hyman-Taylor P, TOPIC Study Group, , et al. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial. Lancet. 2005;365:573–578.
Hong LT, Liou TG, Deka R, et al. Pharmacokinetics of continuous infusion beta-lactams in the treatment of acute pulmonary exacerbations in adult patients with Cystic Fibrosis. Chest. 2018;154:1108–1114.
Crass RL, Pai MP, Lodise TP Jr. Individualizing piperacillin/tazobactam dosing in adult patients with cystic fibrosis: can tobramycin measurements help?. J Antimicrob Chemother. 2019;74:126–129.

VZ8RRZ51VK (Tobramycin)
0 (Anti-Bacterial Agents)

Date Created: 20220907 Date Completed: 20230320 Latest Revision: 20230814

20230815

10.1097/FTD.0000000000001021

36070759