INTERSPECIES COMPARISON OF PHARMACOKINETIC PARAMETERS OF AN ORAL SUSTAINED-RELEASE PREPARATION OF ILOPROST

Iloprost is a chemically stable, pharmacologically highly potent PGl(2)-mimetic for which therapeutic efficacy was proven after iv infusion treatment in PAOD-patients. The development of an oral, therapy facilitating preparation was mainly based on the imitation of plasma levels as obtained after iv to provide an equieffective dosage form. Due to the short half-life in plasma a modified release preparation was formulated. In the present set of experiments the pharmacokinetics of sustained release iloprost in animals and man was investigated after species specifically different dosages. After normalization for the bioavailable fraction of a 150 mu g dose several mean pharmacokinetic parameters were similar in all species with peak plasma levels of 162, 223 and 160 pg/ml (pig, dog, man), t(max)-values of 1.5, 1.9 and 1.6 h, AUC-values of 651, 730 and 763 pg.h/ml. The half-value duration, representing the time of half-maximal plasma levels and thus describing retardation, accounted for 2.8, 2.5 and 2.4 h. For all species a correlation between in-vitro liberation data of the dosage form and drug amount absorbed in-vivo could be shown. Despite differences in gastrointestinal conditions pharmacokinetics was able to demonstrate an interspecies comparability of systemic iloprost levels after intragastric treatment with an extended release preparation of iloprost, which helped to select an optimal formulation variant and to extrapolate toxicological tolerability data for the administration to man. By this strategy a promising oral dosage form could be selected which might be therapeutically equivalent to iv infusion after individual dose titration in patients.