Investigation of pharmacokinetics and drug-drug interactions of melatonin and memantine as components of the new original combination drug Miladean®

Goncharov A.S.: "Serta Clinic", LLC, Moscow

Grigoriev A.: Research Center “Analytical Spectrometry” LLC, Moscow

Globenko A.: “Valenta Pharm” JSC, Moscow, Russia

Goncharov I.S.: "Serta Clinic", LLC, Moscow

Muratov K.A.: "Serta Clinic", LLC, Moscow

Sidorova A.: Research Center “Analytical Spectrometry” LLC, Moscow

Nikitin A.A.: CSU "Analytical Spectrometry" LLC, Moscow

Kapashin A.: “Valenta Pharm” JSC, Moscow, Russia

Kovchan O.: “Valenta Pharm” JSC, Moscow, Russia

Bashkatova A.I.: "Valenta Pharm" JSC, Moscow, Russia

Pasko M.: “Valenta Pharm” JSC, Moscow, Russia

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Summary

Aim

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.

Results

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.

Conclusion

Our study showed favourable tolerability of Miladean® oral dispersible tablets 3 mg + 5 mg and the absence of drug-drug interactions between its components.

Key words

Melatonin, memantine, Miladean®, drug-drug interactions, randomized trial, safety, pharmacokinetics.