PHARMACOKINETICS AND TOLERABILITY OF ORAL ILOPROST IN THROMBOANGIITIS-OBLITERANS PATIENTS

Objective: Iloprost is a potent PGI(2) mimetic, which has been shown t o be therapeutically effective in several vascular disorders. Due to i ts rapid clearance from the central compartment, iloprost is administe red mainly by i.v. infusion, which limits its use to hospitalized pati ents. In order to improve pharmacotherapeutic use of this PGI(2) mimet ic, an oral extended-release (ER) dosage form has been developed, whic h should mimic plasma level profiles as observed after i.v. infusion a nd serve as a therapeutic equivalent. Methods: This trial was performe d to investigate the tolerability and pharmacokinetics of iloprost adm inistered perorally, compared with i.v. infusion, in 12 pa tients suff ering from thromboangiitis obliterans (TAO). A dose titration was carr ied out for 1 week with i.v. iloprost, followed by a p.o. titration an d treatment phase of 3 weeks' duration. Pharmacokinetics was investiga ted at the individually tolerated dose levels; i.e., on days 5-7 (i.v. infusion at 2, 2.5 and 3 ng . kg(-1) . min(-1)), and twice during p.o . treatment after b.i.d. administration of 50, 100, 150, 200 or 300 mu g. Results: Individual tolerability of iloprost varied: 7 patients ou t of 12 tolerated the maximum i.v. dose of 3 ng . kg(-1) . min(-1); si x tolerated the maximum oral dose of 600 mu g. No patients withdrew fr om the study due to adverse events. Flush and headache were the most c ommon adverse events and seemed to be related to the study drug. After i.v. infusion of iloprost, dose-normalized (3 ng . kg(-1) . min(-1)), steady-state plasma levels were 260 pg . ml(-1). Terminal half-life w as 0.57 h. Total clearance ranged from 8 to 17 ml . min(-1) . kg(-1). Peroral administration of the ER formulation resulted in dose-dependen t C-max and AUC values. AUC values of the first and second daily dose interval, i.e., 0-5 h and 5-11 h after first dosing, were almost ident ical. Absolute bioavailability was 24%, with the exception of two pati ents who tolerated only 50 mu g b.i.d. and exhibited a bioavailability of approx. 60%. The AUC values observed in weeks 2 and 4 were identic al, demonstrating low day-to-day variability of iloprost plasma level profiles in TAO patients. Conclusion: Based upon pharmacokinetic data. the ER formulation provides an equivalent to the i.v. infusion of ilo prost and broadens the range of therapy to nonhospitalized patients. T he availability of capsules with 50 and 100 mu g iloprost enables indi vidual dose titration and pharmacotherapy. Beneficial effects, as obse rved with i.v. iloprost in TAO patients, should therefore be achievabl e by peroral pharmacotherapy using the new ER formulation.