Pharmacokinetic comparison between fixed-dose combination of fimasartan/amlodipine 60/10 mg and the corresponding loose combination through partial replicated crossover study in healthy subjects

Combination therapies of antihypertensive drugs are recommended in cases where hypertension is not controlled by monotherapy. This study aimed to compare the pharmacokinetics (PKs) between fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg and the corresponding loose combination. Because of the high intra-subject variability for maximum plasma concentration (C(max)) of fimasartan, a randomized, open-label, 3×3 partial replicated crossover design was adopted. Subjects received a single dose of FDC of fimasartan/amlodipine 60/10 mg or the corresponding loose combination in each period. Blood samples for PK analysis were collected up to 48 hours for fimasartan and 144 hours for amlodipine, respectively. Geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the FDC to the loose combination for C(max) and area under the concentration-time curve from time 0 to the last quantifiable time point (AUC(last)) were calculated. Sixty healthy subjects were randomized, and 57 subjects completed the study. The concentration-time profiles of fimasartan and amlodipine were similar between the FDC and loose combination. The GMRs (90% CIs) of the FDC to the loose combination for C(max) and AUC(last) were 1.0440 (0.9202–1.1844) and 1.0412 (0.9775–1.1090) for fimasartan, and 1.0430 (1.0156–1.0711) and 1.0339 (1.0055–1.0631) for amlodipine, respectively. The GMRs and its 90% CIs for C(max) and AUC(last) of fimasartan and amlodipine were included not only in the scaled bioequivalence criteria but also in the conventional bioequivalence criteria. In conclusion, FDC of fimasartan/amlodipine 60/10 mg showed comparable PK profiles with the corresponding loose combination, which suggests their bioequivalence.

A quantitative approach for cardiovascular safety evaluation of a generic drug

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assess equivalence in pharmacokinetics and safety profiles between test and reference formulations. However, there is no established quantitative approach available for safety assessment. This study aimed to propose a method for drug safety evaluation in generic drug development, as assessed by drug influence on blood pressure and heart rate change. Data were taken from a randomized, open label, 2-way cross-over comparative PK study for megestrol conducted in 39 healthy male volunteers. Vital signs of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parameters used in the analysis were area under vital sign change versus time curve to the last measured time (AUVlast) and maximum vital sign change (Vmax). Considering highly variable nature of vital signs, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule for safety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals of geometric mean ratio for DBP, 0.7969~1.0377 for Vmax and 0.7304~1.0660 for AUVlast, were both included in the equivalence ranges of 0.7694~1.2997 and 0.6815~1.4674, respectively, and similarly, those for HR were included in their respective scaled equivalence limits, while SBP satisfied the conventional equivalence criterion of 0.8-1.25. These results illustrate the feasibility of applying the suggested approach in cardiovascular safety evaluation in a generic drug.