Relevance of preclinical rodent pharmacokinetics in the selection of a companion antibiotic for combining with beta-lactamase inhibitor.

Relevance of preclinical rodent pharmacokinetics in the selection of a companion antibiotic for combining with beta-lactamase inhibitor.
Xenobiotica. 2019 Nov 22;:1-24
Authors: Giri P, Delvadia P, Ladani MK, Prajapati N, Joshi V, Giri S, Patel N, Jain MR, Srinivas NR
Abstract
1. Recent approvals of β-lactamase inhibitor (BLI) drug in combination with cephalosporins/penems have provided the right impetus for novel BLIs. One important research question, hitherto not addressed, is pertaining to the relevance of preclinical pharmacokinetics for pairing the antibiotic with existing/novel BLI.2. Two BLI combination drugs: a) approved (i.e., ceftazidime/avibactam); b) clinical development (i.e., cefepime/zidebactam) were explored to provide insights to address the research question.3. Individual intravenous dosing of ceftazidime, avibactam, cefepime and zidebactam was done at 1 mg/kg by intravenous route in Balb/c mice and Wistar rats. Serial blood samples were collected and analysed by LC-MS/MS method.4. Examination of the ratios of pharmacokinetic parameters (CL, VSS and T1/2) for individual drugs in combinations (for instance: CL (ceftazidime)/CL (avibactam); CL (cefepime)/CL (zidebactam) suggested that the pharmacokinetic data gathered in rats were generally within 0.5 to 2-fold; but mouse data revealed larger disparity for VSS (0.11 to 8.25-fold) or CL (0.49- to 4.03-fold).5. The observed ratio for CL/VSS observed in rats agreed wit...

Source: Xenobiotica - November 21, 2019 Category: Research Authors: Giri P, Delvadia P, Ladani MK, Prajapati N, Joshi V, Giri S, Patel N, Jain MR, Srinivas NR Tags: Xenobiotica Source Type: research