P. T. Pollak,1 N. Dehar,1 R. J. Herman,1 K. B. Zarnke,1 R. D. Feldman2; 1University of Calgary, Calgary, AB, Canada, 2Western University, London, ON, Canada
BACKGROUND: Pharmacy switches among “branded” and generic antihypertensive medications occur frequently. Approval of generic formulations is based on non-time-based pharmacokinetic criteria. In vitro dissolution studies suggesting Mylan-nifedipine ER (MyN) 24-h drug release is only ~80% that of “branded” Adalat XL (AdN) support initial observations of blood pressure (BP) differences between MyN and AdN. A formal study was funded to confirm these observations.
METHODS: A randomized crossover trial with block allocation has studied 10 pts receiving daily morning AdN vs. MyN 60 mg. After each 2-week dosing period, 24-h ambulatory BP was recorded. Systolic (SBP), both for 24 h and the last 8 h (22:00 h - 06:00 h) was examined.
RESULTS: Mean ± SE 24-h SBP was 135 ± 2.6 mmHg with AdN, and 139 ± 2.5 mmHg with MyN (p=0.03). For the last 8 h, mean ± SE nocturnal SBP was 128 ± 4.0 mmHg with AdN and 134 ± 2.9 mmHg with MyN (p=0.02).
CONCLUSION: Mean SBP for 24 h and last 8 h of dosing interval were statistically significantly higher in patients when taking MyN, than when taking AdN. This is likely based on MyN’s first-order drug release profile providing a different temporal distribution of drug concentrations than AdN’s zero-order drug release, over the 24-h (12 half-life) dosing interval, especially at end of dosing interval. Although bioequivalence is approved based on 24-h AUC, differences in both extent and timing of delivery of drug between one style of delivery to the other could allow important concentration fluctuations for a drug with only a 2-hour half-life. This would only be documented with partial AUC analysis. Our results indicate that arbitrary nifedipine switching by pharmacies may lead to unexplained variability in BP control, with unintended consequences for patient risk management.