Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.

Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects.

Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Two Phase 1, randomized, open-label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics.

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.

A phase I, open-label, mass balance study of [(14)C] dacomitinib (PF-00299804) in healthy male volunteers.

Purpose: This study aimed to characterize the primary routes of elimination of the pan-HER tyrosine kinase inhibitor, dacomitinib (PF-00299804), to evaluate the pharmacokinetics of total radioactivity and of dacomitinib and to identify the metabolites of dacomitinib in plasma, urine, and feces in the healthy volunteers.

Methods: Six male healthy volunteers (mean age 31.5 years) received a single 45-mg oral dose containing ~100 μCi [(14)C] dacomitinib.

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers.

Purpose: To evaluate the effect of food on axitinib pharmacokinetics in healthy volunteers with two different crystal polymorphs.

Methods: Two separate open-label, randomized, single-dose, three-period, crossover trials were conducted. Study I, conducted first using 5-mg axitinib Form IV film-coated immediate-release (FCIR) tablets, enrolled 18 subjects to compare fed versus fasted states and 24 subjects to evaluate the effect of timing of food consumption on axitinib pharmacokinetics.

The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers.

Purpose: This study evaluated the effect of a single 45-mg dose of dacomitinib (PF-00299804), an irreversible small-molecule inhibitor of human epidermal growth factor receptors-1, -2, and -4, on CYP2D6 activity in healthy volunteers (HV) using dextromethorphan (DM), a selective CYP2D6 probe.

Methods: Fourteen male HVs were enrolled in this open-label, randomized, cross-over, single-dose study of DM alone or with dacomitinib. Each HV received both treatments separated by a 14-day washout period.

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics.

Objective: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment.

Methods: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed.

Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function.

This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay.