A randomized, open-label 3-way crossover study to investigate the relative bioavailability and bioequivalence of crushed sildenafil 20 mg tablets mixed with apple sauce, extemporaneously prepared suspension (EP), and intact sildenafil 20 mg tablets in healthy volunteers under fasting conditions.

The relative bioavailability and bioequivalence of 20-mg doses of a pediatric formulation of sildenafil extemporaneous preparation suspension (EP; 10 mg/mL), the sildenafil 20-mg intact tablet and the crushed sildenafil 20-mg tablet mixed with apple sauce were assessed in a single-dose, randomized, open-label, 3-way crossover study with 18 healthy adult volunteers. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUCinf ) were used to estimate relative bioavailability and construct 90% confidence intervals (CI) using a mixed-effects model. Bioequivalence was concluded among the three formulations with one exception, in which the EP suspension showed a 15% decrease in Cmax with a lower 90% CI of 76% compared with the intact tablet. The 15% decrease in sildenafil Cmax is not considered to be clinically relevant. Therefore, the EP suspension is considered to be an appropriate pediatric formulation. All 3 formulations were well tolerated in healthy adult volunteers.

A phase I open-label study to investigate the potential drug-drug interaction between single-dose dacomitinib and steady-state paroxetine in healthy volunteers.

Dacomitinib is currently in development for the treatment of non-small cell lung cancer. Formation of the major circulating metabolite (PF-05199265) is mediated by cytochrome P450 (CYP) 2D6 and CYP2C9. This phase I, single fixed-sequence, two-period study evaluated the effect of paroxetine, a CYP2D6 inactivator, on dacomitinib pharmacokinetics in healthy volunteers who were extensive CYP2D6 metabolizers. Subjects received a single 45-mg dacomitinib dose alone and in combination with paroxetine (30 mg/day for 10 consecutive days, with dacomitinib administered on day 4) at steady-state levels. Blood samples were collected through 240 hours post-dacomitinib dosing. Dacomitinib exposure (area under the concentration-time curve from 0 to infinity; AUCinf) increased 37%; however a reduction in PF-05199265 AUCinf of approximately 90% was observed during the paroxetine treatment period. The maximum concentration of dacomitinib changed minimally. Adverse events reported with single-dose dacomitinib administered alone or in the presence of steady-state levels of paroxetine were mostly mild, and no serious adverse events were reported. While paroxetine significantly inhibited CYP2D6-mediated metabolism of a single dose of dacomitinib, the modest effect on dacomitinib exposure is unlikely to be clinically relevant when dacomitinib is given daily. Dose adjustment of dacomitinib may therefore not be required upon coadministration with a CYP2D6 inhibitor.