Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function

Abstract

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL CRs) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL CRs of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL CRs of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC τ) was computed as dose/CL. The probability of achieving an AUC τ/MIC ratio of ≥219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC τ/MIC ratio of ≥219 for MIC values as high as 2 mg/liter. For patients with CL CRs of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC 0-24 (AUC from 0 to 24 h) and AUC 24-48 intervals for MICs of ≤1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC 0-24 and AUC 24-48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate. Copyright © 2012, American Society for Microbiology. All Rights Reserved.