Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis
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This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1–18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 μg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 μg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 μg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 μg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 μg/mL.
KeywordsPseudomonas aeruginosa Aminoglycosides Pharmacometrics NONMEM
The authors would like to thank Stephen B. Duffull, M Pharm (Clin), Ph.D, MPS University of Otago, New Zealand and Barbara Chatfield, M.D. Intermountain Cystic Fibrosis Paediatric Centre, UT, USA for their contributions to this study.
- 4.Cystic Fibrosis Foundation (2007) Cystic Fibrosis Foundation patient registry: 2006 annual data report to the center directors. Cystic Fibrosis Foundation, BethesdaGoogle Scholar
- 13.Chambers HF (2010) Chemotherapy of microbial diseases: aminoglycosides. In: Brunton LL, Chabner BA, Knollman BC (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. The McGraw-Hill Companies Inc, New YorkGoogle Scholar
- 15.Smyth A, Tan KH, Hyman-Taylor P, Mulheran M, Lewis S, Stableforth D, Prof Knox A (2005) Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial. Lancet 365(9459):573–578. doi: 10.1016/S0140-6736(05)17906-9 PubMedGoogle Scholar
- 17.Smyth AR, Bhatt J (2012) Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2:CD002009. doi: 10.1002/14651858.CD002009.pub4
- 23.Burgess DS (2005) Use of pharmacokinetics and pharmacodynamics to optimize antimicrobial treatment of Pseudomonas aeruginosa infections. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 40(Suppl 2):S99–S104. doi: 10.1086/426189 CrossRefGoogle Scholar
- 37.den Hollander JG, Fuursted K, Verbrugh HA, Mouton JW (1998) Duration and clinical relevance of postantibiotic effect in relation to the dosing interval. Antimicrob Agents Chemother 42(4):749–754Google Scholar