A quantitative approach for cardiovascular safety evaluation of a generic drug

다국어 초록 (Multilingual Abstract)

In generic drug development, comparative pharmacokinetic (PK) studies are conducted to assessequivalence in pharmacokinetics and safety profiles between test and reference formulations. However,there is no established quantitative approach available for safety assessment. This study aimedto propose a method for drug safety evaluation in generic drug development, as assessed by druginfluence 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. Vitalsigns of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) weremeasured at 0 (pre-dose), 4, 8, 12, 24, 48, 72, 96 and 120 hours after the dose. Safety parametersused 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 vitalsigns, the scaled bioequivalence approach developed by US FDA was adopted as a decision rule forsafety evaluation between formulations. With the FDA scaled approach, 90% confidence intervals ofgeometric mean ratio for DBP, 0.7969~1.0377 for Vmax and 0.7304~1.0660 for AUVlast, were bothincluded 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 theconventional equivalence criterion of 0.8-1.25. These results illustrate the feasibility of applying thesuggested approach in cardiovascular safety evaluation in a generic drug

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