A quantitative approach for cardiovascular safety evaluation of a generic drug.
10.12793/tcp.2015.23.2.54
- Author:
Mijeong SON
1
;
Yukyung KIM
;
Dong Woo CHAE
;
Kyungsoo PARK
Author Information
1. Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. kspark@yuhs.ac
- Publication Type:Randomized Controlled Trial ; Original Article
- Keywords:
vital signs;
safety evaluation;
quantitative approach;
scaled bioequivalence
- MeSH:
Blood Pressure;
Heart Rate;
Humans;
Male;
Megestrol;
Pharmacokinetics;
Therapeutic Equivalency;
Vital Signs;
Volunteers
- From:Translational and Clinical Pharmacology
2015;23(2):54-58
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
