Assessing the pharmacokinetic drug interaction potential of kratom with drugs of abuse

Rakshit Sanjay Tanna

doi:10.7273/000004985

Kratom, a botanical natural product with opioid-like effects, resembles cannabis in terms of legal status, advocacy, commercial marketing, usage trends, and an overall perception of being harmless among users. The use of kratom to self-treat opioid withdrawal symptoms and pain has greatly increased in western countries. In the US, laws regarding the import, sale, possession, and usage of kratom have been changing based on increasing reports of kratom-associated adverse events. The majority of these adverse events involved polyintoxication-related overdose deaths when kratom was intentionally or unintentionally co-consumed with other drugs. The underlying causes of these kratom-drug interactions remain understudied. Collectively, the objective of this dissertation project was to assess potential pharmacokinetic mechanisms underlying these kratom-drug interactions using a translational research approach. Inhibition of cytochrome P450 (CYP) 2D6 and CYP3A were identified as potential mechanisms underlying pharmacokinetic kratom-drug interactions based on in vitro evidence and clinical case reports reviewed in Chapter 1. An iterative approach involving mechanistic in vitro evaluation, in vitro to in vivo extrapolation, and clinical evaluation was devised to assess the potential for kratom to precipitate pharmacokinetic drug interactions. In Chapter 2, the most abundant kratom alkaloid, mitragynine, was shown to be a strong competitive inhibitor of CYP2D6 and time-dependent inhibitor of CYP3A. Application of the data to an established mechanistic static model predicted mitragynine to increase systemic exposure to the CYP3A probe drug midazolam but not to the CYP2D6 probe drug dextromethorphan, warranting further assessment via a proof-of-concept clinical study. In Chapter 3, the pharmacokinetics of kratom alkaloids, specifically mitragynine, speciogynine, paynantheine, mitraciliatine, speciociliatine, isopaynantheine, and 7-hydroxymitragynine were thoroughly characterized in human participants administered a single low dose (2 g) of kratom as a tea. The pharmacokinetic outcomes were later used to develop and verify physiologically based pharmacokinetic (PBPK) models that can be used to predict other pharmacokinetic kratom-drug interactions. In Chapter 4, as predicted, a single low dose (2 g) of kratom tea administered to healthy adults was shown to increase systemic exposure to midazolam but not to that of dextromethorphan. A fit-for-purpose mitragynine-midazolam PBPK model revealed that the interaction was primarily mediated via inhibition of intestinal CYP3A. In Chapter 5, the fit-for-purpose PBPK model was refined with additional mechanistic details regarding the absorptive permeability and elimination kinetics of mitragynine. The kratom alkaloids paynantheine and speciogynine were identified as additional inhibitors of CYP2D6 and CYP3A and were incorporated into the model. An integrated PBPK interaction model was next developed that can be used to simulate additional pharmacokinetic kratom-drug interactions mimicking typical kratom consumption patterns. This research not only fills multiple knowledge gaps about the drug interaction liability of an emerging botanical product, but the translational approach used could be applied to other natural product-drug interactions. Such evaluations will provide conclusive evidence to consumers, clinicians, and federal regulators about the risk of combining natural products and conventional pharmacotherapeutic regimens.

Assessing the pharmacokinetic drug interaction potential of kratom with drugs of abuse

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