DEVELOPMENT AND APPLICATION OF A PHARMACOKINETIC SIMULATION PROGRAM FOR ORAL CONTROLLED-RELEASE DOSAGE FORMS - DIPS

A pharmacokinetic simulation computer program has been developed to assist in the development of prolonged release dosage forms - Dissolution Input Plasma Simulator (DIPS). DIPS accepts conventional cumulative in vitro release data obtained with a standard dissolution test, without any form of curve fitting, using a simple 'time slicing' procedure. To allow for, and understand, the complex relationship that may exist between release and actual absorption of the drug molecule into the systemic circulation, a series of sequential first order absorption rate constants are set up. The 'sequential absorption profile' (SAP), when optimised and combined with the in vitro dissolution curve, produces a simulated curve giving a good fit to the in vivo profile for that particular product/dissolution test. Entering in different release data (either theoretical or experimental) produces a predicted plasma profile. DIPS generates both single and multiple dose simulations for drugs fitting the one- and two-compartment open models. The program was originally developed for studies on the antihistamine acrivastine. The predictive capabilities of DIPS were assessed using bioavailability data obtained from studies on bupropion, metoprolol, felodipine and paracetamol. With four of these drugs a high degree of correlation was obtained between actual and predicted plasma levels, following the estimation of the SAP for the slowest releasing batch in each study. The lower degree of predictability for felodipine was attributed to the dissolution test, which may have underestimated the in vivo release rate of this extremely insoluble molecule.