生物等效性和生物利用度杂志

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The Pharmacokinetic Properties and Bioequivalence of Methyldopa Formulations: Results of an Open-label, Randomized, Two-period, Crossover, Single-dose Study

Alexander Leonidovich Khokhlov, Leonid Nikolaevich Shitov, Miroslav Ryska, Yuriy Aleksandrovich Dzhurko, Vladimír Kube&scaron, Vitaliy Nikolaevich Shabrov, Aleksey Evgenyevich Miroshnikov, Elena Valeryevna Korneva, Anna Vitalyevna Demchinskaya, Anastasiya Mikhailovna Shitova, Igor Evgenyevich Shokhin and Elena Georgievna Lileeva

Comparative assessment of the pharmacokinetic properties and bioequivalence (BE) of two methyldopa formulations (Methyldopa, 250 mg tablets, R-Pharm CJSC, Russia-investigational medicinal product, and Dopegyt®, 250 mg tablets, EGIS Pharmaceuticals PLC, Hungary-reference product) were investigated in 24 healthy volunteers (13 women and 11 men, caucasian) in an open-label, randomized, crossover, two-period, two-sequence trial with 7-day washout period. A comparative dissolution test was carried out in advance in 3 media, including quantitative determination of methyldopa by UV spectrophotometry. The release patterns of the active ingredient from the test and reference products were equivalent. Methyldopa concentrations in plasma were measured by validated method of high-performance liquid chromatography-tandem mass spectrometry, using the deuterated internal standard. The validation method yields data meeting all acceptance criteria for the plasma methyldopa concentration range of 0.020-3.000 μg/mL. Stabilization of plasma samples was developed that involved addition of ascorbic acid to the plasma during the sampling procedure at the study site. The BE assessment involved calculation of 90% confidence intervals for AUC, Cmax, and Cmax/AUC using analysis of variance (ANOVA) of log-transformed data within an range of 80.00-125.00%. No statistically significant differences were observed between the two drugs. The point estimates and 90% confidence interval limits were as follows: AUC0-t-92.93% (80.69-107.03%), Cmax-94.89% (80.88-111.34%), Cmax/AUC0-t-102.11% (93.95-110.98%), corresponding to the acceptable ranges (80.00-125.00%). The test and reference drug products are characterized by a high degree of pharmacokinetic similarity and thus are bioequivalent.