GENDER SEGREGATION OF 24-H AMBULATORY BLOOD PRESSURE (ABPM) RESPONSE TO SWITCHING BETWEEN DIFFERING NIFEDIPINE OSMOTIC DELIVERY FORMULATIONS

Abstract

Pharmacy initiated switches between “branded” and generic antihypertensive medications happen frequently. Regulatory approval of generic formulations does not require any time-based pharmacokinetic parameters. Therefore, timing of drug release is not evaluated in formulations with modified delivery. To assess clinical differences in blood pressure response in patients being switched between the two available nifedipine formulations: Mylan-nifedipine ER (MyN - labelled KU in Table) vs. “branded” Adalat XL (AdN - labelled GITS in Table), the clinical response was documented using 24-h Ambulatory Blood Pressure Monitoring (ABPM). A randomized crossover, block design was used to study 20 patients receiving daily morning-dosed AdN vs. MyN 60 mg. After each 2-week dosing period, 24-hr ABPM was done. Systolic (SBP) was compared for both 24 h and terminal 8 h (22:00 h - 06:00 h). Mean ± SE 24-h SBP was 133 ± 2.4 mmHg with AdN, vs. 135 ± 2.3 mmHg with MyN (p=0.03). For terminal 8 h, mean ± SE nocturnal SBP was 125 ± 3.3 mmHg with AdN vs. 129 ± 2.8 mmHg with MyN (p=0.018). However when only women were evaluated (see Table), SBP for 24-h was 133 ± 4.0 mmHg with AdN vs. 137 ± 3.3 mmHg with MyN (p=0.0002) and for terminal 8-h, was 124 ± 5.4 mmHg with AdN vs. 132 ± 4.0 mmHg with MyN (p=0.0003). Mean SBP for 24-h and terminal 8-h dosing were statistically significantly higher in patients when taking MyN, than when taking AdN. This is likely based on differences in delivery technology producing temporal differences in distribution of nifedipine concentrations. MyN’s first-order drug release profile is, by design and manufacture, different than AdN’s zero-order drug release. For a drug with only a 2-hour half-life, differences in both extent and timing of delivery could allow important concentration fluctuations in early and late partial AUC’s. Sensitivity to the difference in formulations appears greater in women, especially at the end of the dosing interval. The physiologic basis for this gender difference should be explored further. Arbitrary nifedipine switching by pharmacies may lead to unexplained variability in BP control, with unintended consequences in patient management.