University of Florida Gainesville, Florida, United States
Purpose: Kratom (Mitragyna speciosa Korth.), a tree native to Southeast Asia, is used both recreationally and as a self-treatment for mood elevation, pain relief, and/or mitigation of opioid withdrawal symptoms. Mitragynine is the most abundant kratom alkaloid and among its many pharmacological activities is a partial µ-opioid receptor agonist. Mitragynine is believed to be responsible for the psychoactivity of kratom without deleterious effects associated with typical opioids (1, 2). A pharmacokinetic and pharmacodynamic (PK/PD) model was developed to describe the antinociceptive effect of mitragynine in C57BL/6 mice. Methods: Hotplate antinociception, pharmacokinetics, and brain distribution studies were performed at equianalgesic oral doses of mitragynine. A PK/PD model was developed and further improved to predict the antinociceptive effects after various oral doses of mitragynine using Monolix (version 2020R1) (2). A best-fitted model to describe the observed data was selected based on diagnostic plots and simulations. Results: Mitragynine can cross the blood-brain barrier, and the brain to plasma exposure ratio for mitragynine was 2.0 in mice. The mean metabolite (7-hydroxymitragynine) to parent exposure ratio in the brain was ≤ 2.5% and the maximum brain concentrations (Cmax) of 7-hydroxymitragynine were 0.65 μg/g. Concentration-time data of mitragynine was best described by a two compartmental pharmacokinetic model, and sex was identified as a covariate for clearance (CL/F). A linear PK/PD (percent maximum possible antinociceptive effect, %MPE) relationship was best characterized as a direct-link model where the effect (E) is determined using a sigmoid Emax model. A developed model was used for the prediction of effect (%MPE) effect versus time for the different oral doses of mitragynine and the results of simulations were compared with the observed in vivo findings. Conclusion: A sigmoid Emax model with effect-compartment was well characterized for the antinociceptive effect of mitragynine and model-based predictions along with the pharmacodynamic data in mice provided supportive evidence for the potential of mitragynine to treat pain. Developed PK/PD for mice can be scaled further to predict the mitragynine mediated responses in humans. References: 1. Sharma, A., & McCurdy, C. R. (2021). Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder. Expert Opinion on Drug Metabolism & Toxicology, 17(3), 255-257. 2. Berthold, Erin C., et al. "The Lack of Contribution of 7-Hydroxymitragynine to the Antinociceptive Effects of Mitragynine in Mice: A Pharmacokinetic and Pharmacodynamic Study." Drug Metabolism and Disposition 50.2 (2022): 158-167.
