A Phase 1, Open Label Study To Evaluate The Drug Interaction Potential With Ketoconazole and The Effect Of Food On The Plasma Pharmacokinetics Of The Smoothened Inhibitor PF-04449913

PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK).

This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3.

PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUC_inf (area under the plasma concentration versus time curve from time zero to infinity) and C_max (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUC_inf and C_max for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.

PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUC_inf of 2.40 (90% CI: 2.15 -2.68) and for C_max of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, C_max occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUC_inf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for C_max was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 C_max occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related.

PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUC_inf and 1.40-fold for C_max) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful.

Shaik:Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.