The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag‐time after a high fat breakfast

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Abstract
Aims  The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH‐dependent differences in the in vitro release properties of the two dosage forms.Methods  This was a randomized, open, 4‐way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat® OROS or Slofedipine® XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC‐MS/MS method. Calculation of pharmacokinetic parameters was conducted model‐independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat‐bottomed glass vessels, with various buffer systems covering the entire physiological pH‐range of the gastrointestinal tract.Results  After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,∞) was slightly lower for Slofedipine® XL compared with Adalat® OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine® XL compared with Adalat® OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine® XL which resulted in lag‐times of more than 15 h in 15 out of 24 subjects. Owing to this lag‐time under fed conditions the relative bioavailability of nifedipine from Slofedipine® XL compared with Adalat® OROS was only 28% over the intended dosing interval of 24 h.Conclusions  In this study a dosage form‐dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine® XL and Adalat® OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine® XL is administered after a high‐fat breakfast may be explained by the formulation properties. Slofedipine® XL is an erosive tablet with an acid resistant coating whereas Adalat® OROS is designed with an osmotic push‐pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push‐pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine® XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.