Comparative assessment of the pharmacokinetic properties and bioequivalence (BE) of two methyldopa formulations.
Material and methods
BE of Methyldopa (250 mg tablets, R-Pharm CJSC, Russia – investigational medicinal product) and Dopegyt® (250 mg tablets, EGIS Pharma ceuticals PLC, Hungary – reference product) were studied in 24 healthy volunteers (13 women and 11 men, caucasian) in an open-label, randomized, crossover, two-period, twosequence 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 and 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 a 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 %).
Methyldopa, bioequivalence, pharmacokinetics, arterial hypertension.