An evaluation of the P450 inhibition and induction potential of daptomycin in primary human hepatocytes

Abstract

Two in vitro studies assessed the potential of daptomycin (Cubicin^®), a newly marketed antibiotic, to affect the cytochrome P450 (CYP450) isoforms in primary cultured human hepatocytes. Both induction and inhibition of isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were evaluated. The highest concentrations of daptomycin used in both the induction and inhibition assays were approximately eight-fold higher than the peak total drug concentration (50–60 μg/mL), or the peak free drug concentration (estimated 5–6 μg/mL), in plasma at the clinical dose regimen of 4 mg/kg qd. Results in primary human hepatocytes indicate that daptomycin, at concentrations up to 400 μg total drug/mL, demonstrated no biologically significant induction of any of the CYP450 isoform activities in comparison with the negative control or known inducers. At daptomycin concentrations up to 40 μg free drug/mL, no biologically significant inhibition of the activities of these CYP450 isoforms was observed as compared with known inhibitors. The human hepatocyte results demonstrate that daptomycin has no effects on hepatic CYP450-mediated drug metabolism and, therefore, suggest that daptomycin is unlikely to show potential for pharmacokinetic interactions with concomitantly administered drugs that are metabolized by CYP450 isoforms.

Introduction

Daptomycin is a novel lipopeptide antibiotic with bactericidal activity in vitro against most clinically relevant Gram-positive bacteria [1]. It is comprised of a decanoic acid side chain linked to the N-terminal tryptophan of a cyclic 13-amino acid peptide (Fig. 1). Daptomycin exhibits plasma protein binding of 87–94% across species [5], [6], [11]. Currently, daptomycin (Cubicin^®) is approved in the United States for use in the treatment of certain Gram-positive infections of skin and skin structure, including infections due to antibiotic-resistant organisms.

The pharmacokinetic and toxicologic profiles of daptomycin suggest minimal hepatic involvement. After intravenous administration, daptomycin undergoes limited metabolism. It is eliminated primarily as parent drug, with up to 70–80% of the administered dose recovered intact in the urine, and no metabolites have been identified in the rat, dog, monkey, or humans [12]. Upon repeated administration to rats, daptomycin does not accumulate in the liver or have any toxicological effect on the liver (Cubist unpublished data). Although these findings suggest that daptomycin is unlikely to affect hepatic metabolism, the potential for interactions with concomitantly administered drugs that are metabolized by the liver has not been investigated. Ex vivo evaluations after repeated intravenous administration to rats suggest that daptomycin does not have any biologically significant effect on hepatic CYP450 enzyme activity; however, the analysis included only activities of 7-methoxy coumarin demethylase, 7-ethoxy coumarin deethylase, 7-propoxy coumarin depropylase. The current in vitro investigation was designed to assess the potential of daptomycin to cause clinically significant drug–drug interactions via the inhibition or induction of CYPP450. The effect of daptomycin on the activity of seven key CYP450 isoforms was evaluated in isolated primary human hepatocytes.