Comparison of two marketed nifedipine modified-release formulations: an exploratory clinical food interaction study.
OBJECTIVE
The objective of this study was to compare the in vitro and in vivo characteristics of 2 nifedipine modified-release tablet formulations for once-daily dosing marketed in the European community, which were expected to be bioequivalent.


METHODS
In vitro dissolution was tested at different pH values prior to the clinical part of the study. Either 1 tablet of a test formulation or of the reference formulation, both containing 30 mg nifedipine, were administered to healthy white male volunteers immediately after a high-fat breakfast in a randomized, open-label, 2-period crossover design. Plasma samples obtained over the subsequent period of 48 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical laboratory analysis.


RESULTS
Twelve volunteers were enrolled (median age, 28.0 years [range, 21-42 years]; mean body mass index, 24.2 kg/m(2) [range, 19.3-27.0 kg/m(2)]). In vitro dissolution experiments revealed a significant pH dependency in drug release from the investigational tablets, while the reference tablets were found to have pH-independent dissolution. After oral administration of both tablet formulations in the fed state, marked differences in rate and extent of bioavailability were observed. Geometric mean of AUC(0-last)(test, 504.21 h x ng/mL; reference, 361.28 h x ng/mL) was significantly higher for the test product, with a point estimate of 140% and a corresponding 90% CI of 121% to 161%. For the comparison of Cmax values, geometric means were: test, 76.46 ng/mL; reference, 19.20 ng/mL, with a point estimate of 398% and a CI of 316% to 503%. Thus, a significant difference in rate and extent of bioavailability was observed between the 2 products.


CONCLUSIONS
Although both treatments were well tolerated by all volunteers, the test and reference tablets were found to have different pharmacokinetic properties when administered after a high-fat meal.
Wonnemann
Meinolf
M
SocraTec R&D GmbH, Oberursel, Germany. meinolf.wonnemann@socratec-pharma.de
Schug
Barbara
B
Anschütz
Maria
M
Brendel
Erich
E
De Nucci
Gilberto
G
Blume
Henning
H
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012995:Solubility; D013607:Tablets
D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004041:Dietary Fats; D013607:Tablets; D009543:Nifedipine