Population pharmacokinetic evaluation and optimisation of amikacin dosage regimens for the management of mycobacterial infections

Hinke Siebinga, Fiona Robb, Alison H Thomson

Research output: Contribution to journalArticle

Abstract

Background There is limited information on amikacin pharmacokinetics (PK) and dose requirements in patients with mycobacterial infections.
Objectives To conduct a population PK analysis of amikacin data from patients with mycobacterial infections and compare predicted concentrations from standard and modified dosage guidelines with recommended target ranges.Methods A population PK model was developed using NONMEM. Cmax, Cmin, C1h post infusion (C1h)and AUC0-24 using 15 mg/kg daily (OD), the World Health Organisation (WHO) table, 25 mg/kg thrice weekly (TTW) and modified guidelines were compared using Monte Carlo simulations of 1000 patients.
Results Data were available from 124 patients (684 concentrations) aged 16to 92 years. CL was 4.64 L/h per 100 mL/min CLCR; V was 0.344 L/kg. With OD regimens, Cmax was 35-45 mg/L in 30-35%of patients and 35-50 mg/L in 46-48%; C1hwas 25-40 mg/L in 53-59%. The WHO table produced high Cmax values in patients <60 kg and low in patients >75kg. With TTW dosing, around 30% of Cmax were 65-80 mg/L, 40% were 60-80 mg/L and 48% of C1h were 45-65 mg/L. Increasing the dosage interval for patients with CLCR <50 mL/min reduced Cmin values >2 mg/L from 34% to 25% for OD dosing and18% to 13% for TTW.  In patients whose Cmin was <2 mg/L, 82% of AUC0-24 were 100-300 mg.h/L.
Conclusions Standard amikacin dosing guidelines achieve low percentages of target concentrations for mycobacterial infections. Extending the dosing interval in renal impairment and widening target ranges would reduce the need for dose adjustment.

 

Original languageEnglish
Pages (from-to)2933-2940
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume75
Issue number10
Early online date4 Aug 2020
DOIs
Publication statusPublished - 20 Sep 2020

Keywords

  • mycobacteria
  • amikacin
  • therapeutic drug monitoring
  • dosage guidelines
  • pharmacokinetics
  • population modelling
  • infection

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