Physiologically Based Pharmacokinetic Model for Clinical Translation and Predict...

연구 요약

Physiologically Based Pharmacokinetic Model for Clinical Translation and Prediction of Drug Interaction of the Major Kratom Alkaloid, Mitragynine.

ACS pharmacology & translational science 학술지에 발표된 이 연구는 Chiang YH, Kanumuri SRR, Berthold EC 외 연구팀이 수행하였습니다.

이 연구는 'Physiologically Based Pharmacokinetic Model for Clinical Translation and Prediction of Drug Interaction of the Major Kratom Alkaloid, Mitragynine.'에 대한 과학적 분석을 제공합니다.

핵심 내용

The opioid crisis presents a significant public health issue and underscores the urgency of developing effective treatments for opioid use disorder (OUD). Mitragynine (MTG), the major active alkaloid found in kratom (Mitragyna speciosa), presents as a potential OUD therapy. A physiologically based pharmacokinetic model has been established to support first-in-human (FIH) dose selection and assess potential drug-drug interactions. Extensive physicochemical and in vitro studies were performed to define MTG's pharmacokinetic properties for the model. The model was validated through in vivo pharmacokinetic studies (intravenous and oral) in both male and female Sprague Dawley rats, revealing sex-related pharmacokinetic differences. Further validation in non-rodent models included pharmacokinetic studies in female beagle dogs. Utilizing this model, single and multiple dose simulations of MTG (either as the pure compound or as the major alkaloid present in kratom) administration in humans were conducted, predicting the plasma concentration-time profiles of MTG and its active metabolite, 7-hydroxymitragynine (7-HMG) to facilitate dose selection. The model also evaluates MTG's potential as both a victim and perpetrator in drug interactions, considering its effects with CYP3A4 and CYP2D6 inhibitors and substrates. Simulation results indicate that potent CYP3A4 and CYP2D6 inhibitors have minimal impact on MTG exposure. However, co-administration with CYP3A4 inhibitors leads to a reduction in 7-HMG formation. As a perpetrator, MTG has negligible effects on CYP2D6 substrates but increases midazolam exposure by 2.2 to 2.7-folds. This comprehensive model supports the therapeutic development of MTG.

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