Significant food interactions observed with a nifedipine modified-release formulation marketed in the European Union.
The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets (Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.
Wonnemann
M
M
SocraTec R&D GmbH, Oberursel, Germany. meinolf.wonnemann@socratec-pharma.de
Schug
B
B
Schmücker
K
K
Brendel
E
E
van Zwieten
P A
PA
Blume
H
H
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D019963:Clinical Chemistry Tests; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects; D005062:European Union; D005215:Fasting; D018565:Food-Drug Interactions; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D013058:Mass Spectrometry; D009543:Nifedipine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004041:Dietary Fats; D013607:Tablets; D009543:Nifedipine