088: Developing a Physiologically-based Pharmacokinetic Model Across Various Species Exploring Drug Interaction Potential of Mitragynine

Statement of Purpose, Innovation or Hypothesis: The opioid epidemic presents a pressing national health crisis, marked by escalating mortality rates and economic burdens. However, current treatment for opioid use disorder (OUD) faces challenges due to training and access constraints, highlighting the urgent need for more accessible options. Kratom (Mitragyna speciosa), a popular alternative for pain management and energy enhancement, has shown promise in mitigating opiate withdrawal symptoms and treating OUD. Its primary alkaloid, mitragynine (MTG), acts as a partial μ opioid agonist, offering therapeutic benefits without activating other opioid-related side effects. Despite extensive preclinical research, clinical trials on isolated MTG remain limited. This project aims to develop a physiologically based pharmacokinetic (PBPK) model for MTG and its active metabolite, 7-hydroxymitragynine (7-HMG), to inform dose regimens and assess potential drug interactions in human subjects.

Description of Methods & Materials: While MTG demonstrates a favorable safety profile, 7-HMG shows higher µ-opioid receptor binding affinity than MTG and the abuse potential of 7-HMG raises concern. Therefore, the current PBPK model is structured to simulate the systemic exposure of MTG and monitor its conversion to 7-HMG. The full PBPK model for MTG has been developed in rats, and validated in rats, dogs, and monkeys, then extrapolated to humans using GastroPlus^TM. The disposition of MTG and 7-HMG is assumed to be perfusion-limited models for all tissue compartments except adipose tissue which is a permeability-limited model. MTG elimination is assumed to occur by hepatic metabolism and non-renal clearance. Influential parameters of absorption and distribution used in the model were generated from in-house data, e.g., permeability, blood-to-plasma ratio, plasma fraction unbound, and tissue-to-plasma partition coefficient in different organs. Metabolic parameters for predicting the conversion of MTG to 7-HMG were acquired from in vitro hepatocytes and liver microsomes data.

Data & Results: This model effectively predicts the conversion of MTG to 7-HMG across various species in vivo. Intravenous simulation results indicate that the predicted drug exposure for both MTG and 7-HMG falls within a 2-fold range compared to observed values in different animal models, with a mean absolute percentage error (MAPE) within 50%, meeting acceptable criteria. The model also can be applied to simulate the plasma concentration-time profiles of MTG and 7-HMG after oral dosing of MTG and predict the potential drug-drug interaction regarding MTG as a victim and a perpetrator (CYP3A4 and CYP2D6 inhibitor) for CYP450 in humans. Co-administration of MTG significantly increases midazolam (CYP3A4 substrate) exposure, while atomoxetine (CYP2D6 substrate) exposure remains unaffected¹. Furthermore, multiple-dose ketoconazole (CYP3A4 inhibitor) decreases 7-HMG formation, predominantly metabolized by the CYP3A4 pathway, following oral MTG administration.

Interpretation, Conclusion or Significance: By extrapolating MTG plasma concentrations from both preclinical and clinical studies, this method aids in determining appropriate dose regimens and assessing potential drug interactions crucial for the clinical advancement of MTG.

Disclosures:

Citations/References:

1.         Food and Drug Administration website. https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems. Accessed March 27, 2024.

2.        Tanna, Rakshit S., et al. "Clinical pharmacokinetic assessment of kratom (Mitragyna speciosa), a botanical product with opioid-like effects, in healthy adult participants." Pharmaceutics 14.3 (2022): 620.

3.        Trakulsrichai, Satariya, et al. "Pharmacokinetics of mitragynine in man." Drug design, development and therapy (2015): 2421-2429


Additional Information/Authors: None.