To compare pharmacokinetics and evaluate drug-drug interactions of the studied drug Miladean® oral dispersible tablets 3 mg + 5 mg (JSC Valenta Pharm, Russia) and reference products Akatinol Memantine 10 mg film-coated tablets (Merz Pharma GmbH & Co. KGaA, Germany) and Melaxen 3 mg film-coated tablets (Unipharm Inc., USA).
Material and methods
An open, randomized, four-period, cross-over study was conducted to compare pharmacokinetics of the new fixed-dose combination Miladean® and monocomponent drugs Akatinol Memantine and Melaxen as references. Volunteers were randomized into four groups of six people each according to a dosage regimen: T-R1-R2-R1R2, R1-R2-R1R2-T, R2-R1R2-T-R1 or R1R2-T-R1-R2, where T is Miladean®, R1 is Akatinol Memantine, R2 is Melaxen, R1R2 is a combination of both reference drugs. Plasma melatonin and memantine were measured using pre-validated high performance liquid chromatography (HPLC) with tandem mass spectrometric detection.
Pharmacokinetic parameters of memantine were comparable in healthy volunteers after intake of Miladean® or separate or simultaneous intake of reference drugs. Geometric mean ratios of memantine pharmacokinetic parameters for the test product to the reference product were within the 80.00–125.00% confidence interval (CI) specified for bioequivalence studies. However, geometric mean ratio of melatonin pharmacokinetic parameters for the study drug to the reference drugs were beyond the 80.00–125.00% CI. This might reflect the known physiological variability in melatonin pharmacokinetics. There was a significant decrease in time to maximum concentration of melatonin after intake of Miladean® in comparison with the reference drugs. During the study, there were no adverse events or clinically significant abnormal laboratory findings.
Our study showed favourable tolerability of Miladean® oral dispersible tablets 3 mg + 5 mg and the absence of drug-drug interactions between its components.
Melatonin, memantine, Miladean®, drug-drug interactions, randomized trial, safety, pharmacokinetics.