Gentamicin Pharmacokinetics and Pharmacodynamics during Short-Daily Hemodialysis

Abstract

Background/Aims: 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_dial) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. Methods: 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_dial and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl_s) and central volume of distribution (V_c) and influence of urea removal estimates on Cl_dial 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. Results: A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl_s and Cl_dial were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl_s and V_c. Predialysis every-other-day regimens were as effective (C_max ≥8 mg/l and AUC_{48 h} ≥140 mg·h/l) and less toxic (C_min <2 mg/l and AUC_{48 h} <240 mg·h/l) than postdialysis regimens. Conclusions: Estimated gentamicin Cl_dial is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.

In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model

“…However, large evolutionary steps in membrane materials, such as the step from diacetate membranes such as the Baxter CAHP family to intermediate flow triacetate membranes as the Nipro Sureflux-E and the next step to high flow triacetate membranes such as the Nipro Sureflux-UX (SFUX) family have caused considerable impact on clearance rates, as is shown in Figure 3 . Similar to Decker et al we found overall considerably increased clearance values compared to previous publications ( Decker et al, 2012 ). However, due to the larger membrane area of the dialyzers used in our trial the clearance rates presented in this manuscript are even higher, further supporting administration of high doses of aminoglycosides pre dialysis and complete removal of the drug during hemodialysis, thus reducing toxicity ( Decker et al, 2012 ; Veinstein et al, 2013 ; Vossen and Thalhammer, 2013 ).…”

Antibiotic Dosing for Critically Ill Adult Patients Receiving Intermittent Hemodialysis, Prolonged Intermittent Renal Replacement Therapy, and Continuous Renal Replacement Therapy: An Update

“…52,53 Table 2 summarizes recent PK studies and considerations for a starting point for dosing commonly used antimicrobials in patients receiving PIRRT. 54-78 The supplemental materials discuss the literature in detail for each individual drug.…”

Optimization of anti-infective dosing regimens during online haemodiafiltration

“…Therefore, administering an aminoglycoside prior to dialysis should theoretically allow the achievement of a high peak concentration (thereby enhancing bacterial killing), while subsequent early dialytic clearance should help to minimize the AUC and trough concentrations (thereby limiting toxicity) [32]. However, this point is controversial in the literature, where the Renal Drug Handbook [30] and the Kidney Disease Program [31] advise to administer aminoglycosides after dialysis, presumably based on older studies [33], and more recent studies indicate that aminoglycosides should be administered prior to dialysis [34, 35]. Unfortunately, for most patients with renal impairment, also with RRT, attaining both adequate peak and trough concentrations is unlikely.…”