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Preclinical, Clinical, and Translational Sciences

Translational Pharmacokinetic Assessment of <em>Mitragyna Speciosa</em> (kratom), a Potential Treatment Option for Opioid Use Disorder

(M1330-02-09) Translational Pharmacokinetic Assessment of Mitragyna Speciosa (kratom), a Potential Treatment Option for Opioid Use Disorder

Monday, October 21, 2024
1:30 PM – 2:30 PM MT
Purpose: Kratom (Mitragyna speciosa), known as an herbal medicine indigenous to Southeast Asia, has been used as a self-treatment of pain and mood enhancer in Thailand and Malaysia for centuries. In Western countries, kratom has been recognized as a treatment to ease opioid withdrawal symptoms and opioid use disorder (OUD)1, 2. Mitragynine (MTG), the major bioactive alkaloid of kratom, plays a major role for OUD. MTG has been shown to act as a partial m-opioid receptor agonist, notably devoid of inducing respiratory depression and self-administration tendencies3-6. However, the active metabolite of MTG, 7-hydroxymitragynine (7-HMG) raised concerns. It shows abuse potential, higher µ-opioid receptor binding affinity than MTG, and more potent antinociceptive effects than morphine3, 4, 6-9. Here, we not only performed pharmacokinetic (PK) studies in rats to investigate the drug exposure of MTG and the formation of 7-HMG, but also applied to model-informed drug development (MIDD) helping with dose regimen design and the evaluation of potential drug-drug interaction.

Methods: Intravenous (IV) and oral PK studies of MTG were conducted in rats. For IV injection 1, 5, and 10 mg/kg of MTG were dosed in male rats and 5 mg/kg of MTG was dosed in female rats. For oral study, 50 mg/kg and 20 mg/kg of MTG were administrated to male and female rats, respectively. During the PK study, rats were housed in BASi Culex NxT metabolic cages equipped with an automatic blood sampling system for the duration of the study. Blood samples were collected at pre-dose, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 18 and 24 hours, post-dose into heparinized tubes. Plasma was separated by centrifugation for 10 minutes at 850 x g and 4°C and plasma concentration of MTG and 7-HMG were determined using ultra-performance liquid chromatography-tandem mass spectrometry. The PK parameters were obtained by non-compartmental analysis using Phoenix WinNonlin, version 6.4. For model development, a physiologically based pharmacokinetic (PBPK) model for MTG was developed in rats utilizing PBPK model software (GastroPlusTM), and verified in rats, dogs, and humans using data from the current PK studies and literature10-13. Input parameters used in the model were obtained from in-house data, literature, and prediction software (ADMET PredictorTM). Model performance was evaluated if the simulated PK endpoints (arear under curve (AUC0-t), and peak concentration (Cmax)) were within 0.5 to 2-fold range of the observed end points.

Results: In the PK studies, dose-dependent drug exposure can be observed in IV administrated male rats (AUC0-t were 0.29, 0.83, and 2.58 µg*h/mL after 1, 5, and 10 mg/kg IV dosed of MTG), and sex related differences were observed in the PK parameters. Female rats have higher MTG exposure than male rats. AUC0-t in female rats was 2.4 and 3.3-fold higher than in male rats after IV and oral administration, respectively, and Cmax was 2 times higher in female rats than in male rats. Dose-dependent pharmacokinetics, sex related differences, as well as the conversion of MTG to 7-HMG across various species can be well captured in the developed model. Simulation results indicated that the predicted drug exposure for both MTG and 7-HMG falls within a 2-fold range compared to observed values in preclinical studies and clinical trials. The model can be further applied to predict the systemic exposure of MTG and 7-HMG helping with dose selection as well as predict the potential drug-drug interaction regarding MTG as a victim and a perpetrator for CYP450 in humans.

Conclusion: This MIDD approach of MTG involves developing and applying exposure-based and biological models derived from preclinical and clinical data sources to inform drug development and decision-making of mitragynine.

References: 1. Singh, D.; Narayanan, S.; Vicknasingam, B.; Corazza, O.; Santacroce, R.; Roman‐Urrestarazu, A., Changing trends in the use of kratom (Mitragyna speciosa) in Southeast Asia. Human Psychopharmacology: Clinical and Experimental 2017, 32 (3), e2582.
2. Harun, N.; Kamaruzaman, N. A.; Sofian, Z. M.; Hassan, Z., Mini review: potential therapeutic values of mitragynine as an opioid substitution therapy. Neuroscience Letters 2022, 773, 136500.
3. Obeng, S.; Kamble, S. H.; Reeves, M. E.; Restrepo, L. F.; Patel, A.; Behnke, M.; Chear, N. J.-Y.; Ramanathan, S.; Sharma, A.; León, F., Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids. Journal of medicinal chemistry 2019, 63 (1), 433-439.
4. Váradi, A.; Marrone, G. F.; Palmer, T. C.; Narayan, A.; Szabó, M. R.; Le Rouzic, V.; Grinnell, S. G.; Subrath, J. J.; Warner, E.; Kalra, S., Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. Journal of medicinal chemistry 2016, 59 (18), 8381-8397.
5. Yue, K.; Kopajtic, T. A.; Katz, J. L., Abuse liability of mitragynine assessed with a self-administration procedure in rats. Psychopharmacology 2018, 235, 2823-2829.
6. Hemby, S. E.; McIntosh, S.; Leon, F.; Cutler, S. J.; McCurdy, C. R., Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7‐hydroxymitragynine. Addiction Biology 2019, 24 (5), 874-885.
7. Kamble, S. H.; León, F.; King, T. I.; Berthold, E. C.; Lopera-Londoño, C.; Siva Rama Raju, K.; Hampson, A. J.; Sharma, A.; Avery, B. A.; McMahon, L. R., Metabolism of a kratom alkaloid metabolite in human plasma increases its opioid potency and efficacy. ACS pharmacology & translational science 2020, 3 (6), 1063-1068.
8. Matsumoto, K.; Horie, S.; Ishikawa, H.; Takayama, H.; Aimi, N.; Ponglux, D.; Watanabe, K., Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life sciences 2004, 74 (17), 2143-2155.
9. Matsumoto, K.; Horie, S.; Takayama, H.; Ishikawa, H.; Aimi, N.; Ponglux, D.; Murayama, T.; Watanabe, K., Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. Life sciences 2005, 78 (1), 2-7.
10. Maxwell, E. A.; King, T. I.; Kamble, S. H.; Raju, K. S. R.; Berthold, E. C.; León, F.; Avery, B. A.; McMahon, L. R.; McCurdy, C. R.; Sharma, A., Pharmacokinetics and safety of mitragynine in beagle dogs. Planta medica 2020, 86 (17), 1278-1285.
11. Tanna, R. S.; Nguyen, J. T.; Hadi, D. L.; Manwill, P. K.; Flores-Bocanegra, L.; Layton, M. E.; White, J. R.; Cech, N. B.; Oberlies, N. H.; Rettie, A. E., Clinical pharmacokinetic assessment of kratom (Mitragyna speciosa), a botanical product with opioid-like effects, in healthy adult participants. Pharmaceutics 2022, 14 (3), 620.
12. Trakulsrichai, S.; Sathirakul, K.; Auparakkitanon, S.; Krongvorakul, J.; Sueajai, J.; Noumjad, N.; Sukasem, C.; Wananukul, W., Pharmacokinetics of mitragynine in man. Drug design, development and therapy 2015, 2421-2429.
13. Huestis, M. A.; Brett, M. A.; Bothmer, J.; Atallah, R., Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder. Molecules 2024, 29 (5), 984.


Predicted versus observed plasma concentration values of (A) MTG and (B) 7-HMG after intravenous administration of MTG; (C) MTG and (D) 7-HMG after oral single dosing of MTG; (E) MTG after oral multiple dosing of MTG in different species. The black solid lines mark the lines of identity. Black dotted lines indicate 2-fold, black dashed lines indicate 1.25-fold deviation.