Effect of food and gender on the pharmacokinetics of RP 73401, a phosphodiesterase IV inhibitor

Objective: Early exploratory clinical pharmacokinetic studies can provide v aluable information for the design and control of subsequent phase 2 studie s. This philosophy was instituted for the compound RP 73401, a specific pho sphodiesterase IV inhibitor, that was being developed simultaneously for de livery by both oral and pulmonary routes of administration. The objective o f these studies was to separately evaluate the effect of food and gender on the pharmacokinetics of RP 73401 using small-scale focused pilot studies. Methods: In the first study, 400 meg of inhaled RP 73401 were administered to male and female healthy volunteers (n = 8 f, 8 m. Tn the second study, 4 00 meg oral RP 73401 were administered to healthy male volunteers (n = 8) i n the fed and fasted state in a crossover fashion. Serial plasma samples we re collected for 24 hours and analyzed for RP 73401 using an HPLC method wi th post-column photochemical reaction and fluorescence detection that had a minimum quantifiable limit of 10 pg/ml. Pharmacokinetic parameters were ca lculated using non-compartmental technique. Results: Comparison of male and female pharmacokinetics following inhalation administration showed no stat istically significant differences in the absorption and disposition of RP 7 3401 with respect to AUG, C-max, t(max), and t1/2 values. Conversely, RP 73 401 administered subsequently to a high fat meal showed a 51% reduction in C-max and a 5-fold prolongation in t(max) as compared to the fasted state. However, there was no statistically significant difference in the systemic availability of RP 73401 as assessed through AUC(0-infinity) comparisons. C onclusions:These results successfully allowed the uncomplicated inclusion o f females in oral and inhalation studies with RP 73401 and indicated the ne ed to address oral drug dosing conditions in older to minimize sources of p harmacokinetic. variability in subsequent phase 2 studies.