Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies

Satsuki Hashimoto,Ko Misaka,Hiroyuki Tsuchiya,Kyoko Honda,Takumi Taniguchi,Kohei Fujita,Yoshimichi Sai,Yukio Kato,Yuka Miyachi,Yukio Suga,Kazuya Isoda,Satoshi Kato,Tsutomu Shimada,Masaki Okajima

doi:10.1186/s40780-018-0123-1

Satsuki Hashimoto, Ko Misaka + Show 12 more

Open Access

https://doi.org/10.1186/s40780-018-0123-1

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Abstract

BackgroundCombination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown.MethodsWe conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine.ResultsOur clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2.ConclusionsTherapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD.Trial registrationUMIN, UMIN000004322. Registered 4 October 2010.

Highlights

Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains
Studies suggested that therapeutic drug monitoring (TDM) and dose adjustment based on body weight might be unnecessary during LZD therapy
It has been reported that rifampicin (RFP) decreases LZD exposure in terms of trough concentration (Cmin), maximum concentration (Cmax) and area under the concentration-time curve (AUC), and RFP reduced the incidence of LZD-induced thrombocytopenia and/or anemia [12,13,14,15]

Summary

Introduction

Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. Linezolid (LZD) is an oxazolidinone antimicrobial agent with broad-spectrum activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium [1]. It is rapidly absorbed after oral administration, with 100% bioavailability (F), and is metabolized by nonenzymatic oxidation into two inactive metabolites, without the involvement of any major cytochrome P450 (CYP) [2,3,4]. There are several reports of drug-drug interactions (DDI) with LZD in humans: coadministration of omeprazole, amiodarone, amlodipine, sertraline or clarithromycin with LZD increased the exposure to LZD [9,10,11]. It seems necessary to monitor LZD concentration during administration, and to identify the mechanisms involved in these DDIs

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