Population pharmacokinetic evaluation and optimization 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, concentration 1 h post-infusion (C1h) and AUC0-24 using 15 mg/kg daily (once daily), the WHO table, 25 mg/kg three times weekly (TTW) and modified guidelines were compared using Monte Carlo simulations of 1000 patients. RESULTS: Data were available from 124 patients (684 concentrations) aged 16-92 years. CL was 4.64 L/h per 100 mL/min CLCR; V was 0.344 L/kg. With once-daily regimens, Cmax was 35-45 mg/L in 30%-35% of patients and 35-50 mg/L in 46%-48%; C1h was 25-40 mg/L in 53%-59%. The WHO table produced high Cmax values in patients <60 kg and low in patients >75 kg. With TTW dosing, around 30% of Cmax values 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 once-daily dosing and from 18% to 13% for TTW. In patients whose Cmin was <2 mg/L, 82% of AUC0-24 values 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 date3 Aug 2020
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

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

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