Gentamicin Pharmacokinetics and Pharmacodynamics during Short-Daily Hemodialysis

Abstract

<b><i>Background/Aims:</i></b> Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl<sub>dial</sub>) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. <b><i>Methods:</i></b> Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl<sub>dial</sub> and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl<sub>s</sub>) and central volume of distribution (V<sub>c</sub>) and influence of urea removal estimates on Cl<sub>dial</sub> were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. <b><i>Results:</i></b> A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl<sub>s</sub> and Cl<sub>dial</sub> were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl<sub>s</sub> and V<sub>c</sub>. Predialysis every-other-day regimens were as effective (C<sub>max</sub> ≥8 mg/l and AUC<sub>48 h</sub> ≥140 mg·h/l) and less toxic (C<sub>min</sub> <2 mg/l and AUC<sub>48 h</sub> <240 mg·h/l) than postdialysis regimens. <b><i>Conclusions:</i></b> Estimated gentamicin Cl<sub>dial</sub> is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.