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

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.

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“…Linezolid is an oxazolidinone protein synthesis inhibitor that is sometimes combined with the transcriptional inhibitor, rifampicin, for the treatment of S. aureus infections 29,30 . Linezolid/rifampicin reduced viable cells within the biofilm by almost 3-logs but was not significantly potentiated by US-PCCA.…”

Why Product Information Should not be Set in Stone: Lessons from a Decade of Linezolid Therapeutic Drug Monitoring: An Opinion Paper

“…Hashimoto et al demonstrated in animal studies that although the AUC, Cmax, and bioavailability of oral linezolid were reduced by rifampicin by 48%, 54%, and 48%, respectively, no impact was detected on the intravenously administered drug, although this difference was not attributed to altered intestinal permeability. 54 Similarly, animal studies by Okazaki et al 55 reported that the combination of linezolid with rifampicin inhibited its absorption and promoted its elimination, but not via the microsomal enzyme system. They rather suggested that the combination of linezolid and rifampicin reduced linezolid blood concentrations through metabolic enzyme pathways.…”

The Issue of Pharmacokinetic-Driven Drug-Drug Interactions of Antibiotics: A Narrative Review

“…Consistent evidence is now available showing that concomitant administration of rifampicin can significantly reduce the systemic exposure of linezolid, with effect that may persist for up to 2 weeks after rifampicin discontinuation [ 60 , 61 , 62 ]. In vitro studies documented that rifampicin-inducible drug-metabolizing enzymes have a very minor contribution to linezolid clearance.…”

“…In vitro studies documented that rifampicin-inducible drug-metabolizing enzymes have a very minor contribution to linezolid clearance. A large increase in expression of an enzyme (e.g., CYP3A4) that normally plays a relatively modest role in linezolid elimination and/or rifampicin-induced high expression of transport proteins (i.e., p-glycoprotein) have been hypothesized as causes for the observed reduction of linezolid concentrations [ 60 , 61 , 62 ].…”