Clinical Pharmacokinetic Drug Interaction Potential of MenoAct851 in Adult, Female Healthy Volunteers

Vijayakumar Thangavel Mahalingam; Ilango Kaliappan; Satish Kumar Rajappan Chandra; Melvin George; Mohan Kumar Ramasamy; Sarvesh Sabarathinam; Dubey Govind Prasad

doi:10.1016/j.curtheres.2020.100619

Clinical Pharmacokinetic Drug Interaction Potential of MenoAct851 in Adult, Female Healthy Volunteers

Curr Ther Res Clin Exp. 2020 Dec 8:94:100619. doi: 10.1016/j.curtheres.2020.100619. eCollection 2021.

Authors

Vijayakumar Thangavel Mahalingam¹, Ilango Kaliappan², Satish Kumar Rajappan Chandra³, Melvin George⁴, Mohan Kumar Ramasamy³, Sarvesh Sabarathinam¹, Dubey Govind Prasad⁵

Affiliations

¹ Department of Pharmacy Practice, SRM College of Pharmacy, SRM Institute of Science and Technology, Tamil Nadu, India.
² Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Interdisciplinary Institute of Indian System of Medicine, Tamil Nadu, India.
³ Interdisciplinary Institute of Indian System of Medicine, SRM Institute of Science and Technology, Tamil Nadu, India.
⁴ Department of Clinical Pharmacology, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Tamil Nadu, India.
⁵ National Facility for Tribal and Herbal Medicine, Institute of Medical Sciences, Banaras Hindu University, Uttar Pradesh, India.

Abstract

Background: MenoAct851 (Varanasi BioResearch Pvt. Ltd., Varanasi, India) is a patented polyherbal formulation developed to manage menopause symptoms that can be taken along with other allopathic medicines.

Objective: The present study aims to evaluate the drug interaction potential of MenoAct851 to inhibit cytochrome (CY) P450 in vitro in rats, and to measure its effects on simvastatin pharmacokinetic parameters in healthy human volunteers.

Methods: CYP450-carbon monoxide assay of MenoAct851 was performed in rat liver microsomes to calculate the percentage inhibition. Fluorometric assays of CYP3A4 and CYP2D6 determined half maximal inhibitory concentration value. A double-blind, randomized, placebo-controlled drug interaction study of MenoAct851 was conducted in 24 healthy adult female volunteers aged 25 to 50 years. The selected volunteers were randomized to receive placebo or MenoAct851 500 mg BID PO for 14 days. On the 15th day, each group received 40 mg single-dose simvastatin. Blood samples were drawn at different intervals to measure simvastatin pharmacokinetic parameters.

Results: The mean (SD) CYP450 concentration of the diluted microsome sample was calculated and found to be 0.405 (0.12) nmol/mg. The inhibitory potential of MenoAct851 (41.16% [1.24%]) was found to be less than ketoconazole. Half maximal inhibitory concentration values of MenoAct851 on CYP3A4 and CYP2D6 were 11.96 (1.04) µg/mL and 15.24 (0.58) µg/mL, respectively, but they were higher than respective positive controls. There was no statistically significant difference between MenoAct851 and placebo groups concerning the pharmacokinetic parameters such as C_max, T_max, t_½, and mean residence time of simvastatin; however, AUC showed a significant difference (P < 0.05) between the groups.

Conclusions: MenoAct851 produced weaker interaction potential with CYP3A4 and CYP2D6 substrates based on in vitro assays, but the findings of clinical pharmacokinetic analysis indicate that MenoAct851 increased the AUC of simvastatin and simvastatin hydroxy acid. Therefore, coadministration of MenoAct851 might lead to drug-herb interaction, thereby affecting the therapeutic effect of CYP3A4 substrates. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Keywords: CYP450 inhibition; clinical pharmacokinetics; drug-herb interactions; drug-metabolizing enzymes; high throughput fluorometric assay.