Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling
Our objective was to determine the population pharmacokinetic parameters of amikacin in pediatric patients to contribute to the future development of a revised optimum dose and population-specific dosing regimens.
We performed a retrospective chart review in non-critical pediatric patients (aged 1–12 years) who received amikacin for suspected or proven Gram-negative infection at a university hospital. The population pharmacokinetic models were developed using Monolix 4.4. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets.
The analysis included 134 amikacin plasma concentrations from 67 patients with a mean ± standard deviation age of 4.1 ± 3.9 years and bodyweight of 15 ± 8.4 kg. The patients received an amikacin total daily dose (TDD) of 23 ± 7.3 mg/kg, which resulted in peak and trough concentrations of 20.65 ± 7.6 and 2.4 ± 1.7 mg/l, respectively. The estimated pharmacokinetic parameters for amikacin were 1.2 l/h and 6.5 l for total body clearance (CL) and the volume of distribution (V), respectively. Dosing simulations showed that the standard dosing regimen (15 mg/kg/day) of amikacin achieved the PK/PD target of peak serum concentration (Cpeak)/minimum inhibitory concentration (MIC) ≥ 8 for an MIC of 2 mg/l; higher doses were required to achieve higher MIC values.
The simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.
Compliance with Ethical Standards
The authors acknowledge financial support from the College of Pharmacy Research Center and the Deanship of Scientific Research, King Saud University (Riyadh, Saudi Arabia).
Conflict of interest
Saeed Alqahtani, Manal Abouelkheir, Abdullah Alsultan, Yasmine Elsharawy, Aljawharah Alkoraishi, Reem Osman, and Wael Mansy have no conflicts of interest.
- 5.Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;07(1):CD003344.Google Scholar
- 9.Beaucaire G, Leroy O, Beuscart C, Karp P, Chidiac C, Caillaux M. Clinical and bacteriological efficacy, and practical aspects of amikacin given once daily for severe infections. J Antimicrob Chemother. 1999;127(Suppl C):91–103.Google Scholar
- 22.FerriolsLisart R, AlosAlminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Ph. 1996;53(10):1141–50.Google Scholar
- 28.Tam VH, Ledesma KR, Vo G, Kabbara S, Lim TP, Nikolaou M. Pharmacodynamic modeling of aminoglycosides against Pseudomonas aeruginosa and Acinetobacter baumannii: identifying dosing regimens to suppress resistance development. Antimicrob Agents Chemother. 2008;52(11):3987–93.CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Gonzalez LS 3rd, Spencer JP. Aminoglycosides: a practical review. Am Fam Phys. 1998;58(8):1811–20.Google Scholar
- 42.The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0, 2018. http://www.eucast.org.