Assessing transporter-mediated rifampin-linezolid interaction using physiologica...

연구 요약

Assessing transporter-mediated rifampin-linezolid interaction using physiologically-based pharmacokinetic modelling.

British journal of clinical pharmacology 학술지에 발표된 이 연구는 Nguyen HD, Pham VH, Hoglund RM 외 연구팀이 수행하였습니다.

이 연구는 'Assessing transporter-mediated rifampin-linezolid interaction using physiologically-based pharmacokinetic modelling.'에 대한 과학적 분석을 제공합니다.

핵심 내용

AIMS: The study aims to develop a physiologically-based pharmacokinetic (PBPK) model to quantitatively evaluate the role of ATP-binding cassette sub-family B member 1 (ABCB1) and ATP-binding cassette super-family G member 2 (ABCG2) in the drug-drug interaction (DDI) between rifampin and linezolid and to predict the impact of high-dose rifampin on linezolid pharmacokinetics (PK). METHODS: We developed a PBPK model of linezolid and verified this using published clinical PK data. The built-in PK-SIM PBPK model for rifampin was used as a perpetrator model, which incorporate ABCB1 and ABCG2 transporter activity, along with inhibition and induction kinetic parameters. Using the developed PBPK models, linezolid PK was predicted when co-administered with rifampin and verified using published data. Based on the developed DDI model, linezolid exposure when co-administered with high-dose rifampin at steady state was predicted. RESULTS: The developed linezolid PBPK model had acceptable predictive performance for 36 different PK arms from 13 individual clinical studies. The PBPK-predicted DDI effect of standard dose rifampin on linezolid, with AUC and Cmax ratios of 0.77 and 0.87, respectively, aligned well with observed DDI ratio. PBPK simulations indicated that both ABCG2 and ABCB1 contributed to the DDI between linezolid and rifampin, with ABCB1 playing the major role in the interaction. Increasing the daily dose of rifampin from 10 mg/kg to 20-40 mg/kg resulted in a similar linezolid exposure. CONCLUSIONS: Our study suggested that ABCB1 is the primary transporter responsible for the interaction between rifampin and linezolid. The DDI effect of high-dose rifampin on linezolid plasma exposure is similar to that of standard-dose rifampin.

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