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

Objective: Early exploratory clinical pharmacokinetic studies can provide valuable information for the design and control of subsequent phase 2 studies. This philosophy was instituted for the compound RP 73401, a specific phosphodiesterase IV inhibitor, that was being developed simultaneously for delivery by both oral and pulmonary routes of administration. The objective of 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 mcg of inhaled RP 73401 were administered to male and female healthy volunteers (n = 8 f, 8 m. In the second study, 400 mcg oral RP 73401 were administered to healthy male volunteers (n = 8) in the fed and fasted state in a crossover fashion. Serial plasma samples were collected for 24 hours and analyzed for RP 73401 using an HPLC method with post-column photochemical reaction and fluorescence detection that had a minimum quantifiable limit of 10 pg/ml. Pharmacokinetic parameters were calculated using non-compartmental techniques. Results: Comparison of male and female pharmacokinetics following inhalation administration showed no statistically significant differences in the absorption and disposition of RP 73401 with respect to AUC, C max , t max , and t 1/2 values. Conversely, RP 73401 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- ∞ comparisons. Conclusions: These results successfully allowed the uncomplicated inclusion of females in oral and inhalation studies with RP 73401 and indicated the need to address oral drug dosing conditions in order to minimize sources of pharmacokinetic variability in subsequent phase 2 studies.