DIFFERENCES IN BIOAVAILABILITY OF NIFEDIPINE OSMOTIC PUSH-PULL SYSTEMS: PREDICTIVE RESULTS FROM IN-VITRO COMPARED TO IN-VIVO: PP.38.496

Abstract

Two similar osmotic push-pull systems were investigated in-vitro and compared to in-vivo PK data obtained in healthy subjects. Reference contains a bilayer core and Test contains a monolayer core. Identical batches were used for in-vitro and in-vivo testing of the products having a marketing authorisation in Canada. In-vitro dissolution tests over 24 hours were performed prior to the study. The clinical study was conducted in a 4-period crossover design with 26 subjects. Investigations were performed under fasting or fed conditions. Accumulated 24-hour in-vitro tests were performed using USP paddle apparatus in 900 mL surfactant-containing buffer under sink conditions at 37°C. 12 tablets of each product were investigated. Samples were taken every 60 minutes and nifedipine concentration was determined using HPLC. After oral administration, blood samples were taken until 48 h post dosing. Quantification in plasma was performed using validated HPLC-MS/MS method. PK parameters were determined model-independently for each treatment directly from measured concentrations. In-vitro profiles of Test and Reference indicated deviations in initial and terminal release of nifedipine with later onset and lower quantity of drug release for Test, which were confirmed by the findings obtained from in-vivo investigations. Test showed a delayed onset of absorption combined with a later achievement of the plateau phase. Parameter for early exposure, AUC0-tmax(Ref) differed between both products by almost a factor of two. Under fasting condition, Cmax–values obtained were equivalent, but for total exposure, determined as AUC0-tlast, 90% confidence intervals for mean ratio Test/Reference surpsed acceptance range and bioequivalence could not be shown. Confirmation of bioequivalence was not possible under fed condition, where point estimates indicated a reduction of almost 20% and confidence intervals did not include 100%. Differences in completeness of delayed onset and drug release from monolayer system as observed in-vitro is obviously relevant for in-vivo performance and led to delayed onset of absorption and lower exposure, especially under fed condition. These significant differences may have clinical implications for blood pressure control.