Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib.

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.

Evaluation of Proton Pump Inhibitor Esomeprazole on Crizotinib Pharmacokinetics in Healthy Participants.

Crizotinib is a small-molecule, multitargeted tyrosine kinase inhibitor that exhibits decreased aqueous solubility at a higher pH. This open-label, randomized, phase 1 study (NCT01549574) evaluated the effect of multiple doses of the proton pump inhibitor esomeprazole on the pharmacokinetics (PK) of crizotinib and the safety of crizotinib with or without esomeprazole in healthy adults. Participants received a single 250-mg crizotinib dose after overnight fast or a single 250-mg crizotinib dose following esomeprazole 40 mg/day for 5 days. After a washout of ≥14 days, participants crossed over to the alternate treatment. Blood samples for plasma analysis were taken up to 144 hours after crizotinib dosing and relevant PK parameters estimated. Safety was assessed in all participants receiving ≥1 dose of study medication. Fifteen participants were evaluable for PK and safety for each treatment. Coadministration with esomeprazole resulted in a slight decrease (≈10%) in the crizotinib geometric mean area under the plasma concentration-time profile from time 0 to infinity (adjusted geometric mean ratio, 89.81% [90% confidence interval, 79.05-102.03]). Coadministration of esomeprazole did not affect peak crizotinib exposure. Adverse events (AEs) occurred in similar numbers between treatments; no serious or severe AEs occurred. The most common AE was diarrhea. Although esomeprazole decreased total exposure of crizotinib, it is not considered clinically meaningful, and dose modification is not required when crizotinib is coadministered with agents that affect gastric pH.

Effects of Renal Function on Crizotinib Pharmacokinetics: Dose Recommendations for Patients with ALK-Positive Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVES: Crizotinib (250 mg twice daily) is the first anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small-cell lung cancer (NSCLC). The objectives of the current study were to evaluate the effects of mild, moderate, and severe renal impairment on crizotinib pharmacokinetics and to make crizotinib dosing recommendations for ALK-positive NSCLC patients with renal impairment on the basis of the findings. METHODS: The effects of varying degrees of renal impairment on crizotinib pharmacokinetics were evaluated by: (1) analysis of mild and moderate renal impairment on multiple-dose pharmacokinetics of crizotinib in ALK-positive NSCLC patients from the PROFILE 1001 and PROFILE 1005 trials; (2) analysis of severe renal impairment on single-dose pharmacokinetics of crizotinib in volunteers (Study 1020); and (3) prediction of the effect of severe renal impairment on multiple-dose crizotinib pharmacokinetics using a physiologically-based pharmacokinetic model of crizotinib. RESULTS: No clinically relevant changes in plasma crizotinib exposure were observed in NSCLC patients with mild or moderate renal impairment. After a single 250-mg dose, the area under the plasma concentration-time curve (AUC) for crizotinib was 1.8-fold greater in subjects with severe renal impairment than in those with normal renal function. Physiologically-based pharmacokinetic modeling indicated a similar increase in steady-state AUC after multiple dosing. CONCLUSIONS: These results suggest no dose adjustment for patients with mild or moderate renal impairment. The recommended crizotinib dose for patients with severe renal impairment not requiring dialysis is 250 mg once daily.

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 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required.

Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects.

Crizotinib (Xalkori®) is an orally administered, selective, small-molecule, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor/hepatocyte growth factor receptor tyrosine kinases, and has recently been approved for the treatment of ALK-positive non-small cell lung cancer. The absolute bioavailability of crizotinib, effect of a high-fat meal on crizotinib pharmacokinetics (PK), and bioequivalence of several oral formulations (powder in capsule [PIC], immediate-release tablet [IRT], and commercial formulated capsule [FC]) were evaluated in two phase I clinical studies involving healthy volunteers who received single doses of crizotinib. PK parameters for crizotinib and its metabolite, PF-06260182, were determined using non-compartmental methods. The absolute oral bioavailability of crizotinib was approximately 43%, with a slight decrease in crizotinib exposures (area under the plasma concentration-time profile and maximum plasma concentration) following a high-fat meal that was not considered clinically meaningful. The FC was bioequivalent to the clinical development IRT and PIC formulations. No serious adverse events were observed during either study and the majority of adverse events were mild, the most common being diarrhea. Single-dose crizotinib could be safely administered to healthy subjects.

Effect of race and sex on single and multiple dose pharmacokinetics of desloratadine.

OBJECTIVE: This study was designed to characterise the single and multiple dose pharmacokinetic profile of desloratadine, a new antihistamine, and its main metabolite, 3-hydroxy (3-OH) desloratadine, in healthy volunteers differing in sex and race. DESIGN: An open-label, parallel-group, single- and multiple-dose pharmacokinetic trial. INTERVENTION: A single 7.5mg oral tablet of desloratadine on day 1, followed by 7.5mg daily doses on days 4 to 17. PARTICIPANTS: 48 healthy, nonsmoking volunteers (12 White men, 12 Black men, 12 White women, 12 Black women). MAIN OUTCOME MEASURES: AUC(24h) and C(max) determined from serial blood samples of desloratadine and 3-OH desloratadine. RESULTS: There were no clinically relevant differences between men and women or Black participants and White participants for desloratadine and 3-OH desloratadine maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC). Following multiple doses, the geometric mean C(max) was 5.17 microg/L in men, 5.68 microg/L in women, 5.87 microg/L in Black participants and 5.00 microg/L in White participants; the corresponding AUC from 0 to 24 hours (AUC(24h)) values were 77.9, 80.0, 90.6 and 68.8 micro g/L x h. Corresponding 3-OH desloratadine geometric mean C(max) values were 1.93, 2.79, 2.20 and 2.45 microg/L, and the AUC(24h) values were 32.1, 47.5, 37.1 and 41.1 microg/L. h. CONCLUSIONS: Oral administration of multiple doses of desloratadine 7.5mg, a dose 50% higher than the recommended 5mg clinical dose, was well tolerated by healthy adults differing in sex and race. Comparison of the C(max) and AUC values following 14 days of treatment with desloratadine indicates that no dosage adjustment is needed on the basis of sex or race.

Pharmacokinetic interaction between ezetimibe and lovastatin in healthy volunteers.

BACKGROUND: Ezetimibe (Zetia) is a novel inhibitor of intestinal absorption of cholesterol that is approved for the treatment of primary hypercholesterolemia. In a separate pilot study, co-administration of ezetimibe and lovastatin resulted in a significant pharmacodynamic interaction, leading to an additive reduction in LDL-C. The current study was designed to further investigate the potential for pharmacokinetic interaction between ezetimibe and lovastatin. METHODS: This was a randomized, open-label, 3-way crossover study in 18 healthy adult volunteers. All subjects received the following treatments orally once daily for 7 days: ezetimibe 10 mg, lovastatin 20 mg, or ezetimibe 10 mg plus lovastatin 20 mg. Plasma samples obtained on day 7 were evaluated for steady-state pharmacokinetics of ezetimibe (unconjugated), total ezetimibe (ezetimibe and ezetimibe-glucuronide conjugate), lovastatin, and beta-hydroxylovastatin. RESULTS: Co-administration of ezetimibe with lovastatin did not affect the pharmacokinetics of ezetimibe. There were no significant differences in the exposure to total ezetimibe, ezetimibe-glucuronide and ezetimibe after co-administration with lovastatin vs. ezetimibe given alone. Co-administration of ezetimibe with lovastatin had no significant effect on the exposure to either lovastatin or beta-hydroxylovastatin. The point estimates based on the log-transformed Cmax and AUC values for lovastatin and beta-hydroxylovastatin were 113% and 119%, respectively, for co-administration of ezetimibe with lovastatin vs. lovastatin administration alone. Co-administration therapy with ezetimibe and lovastatin was safe and well tolerated. CONCLUSIONS: Ezetimibe did not significantly affect the pharmacokinetics of lovastatin or beta-hydroxylovastatin and vice versa. Co-administration of ezetimibe and lovastatin is unlikely to cause a clinically significant pharmacokinetic drug interaction.

Pharmacodynamic interaction between ezetimibe and rosuvastatin.

BACKGROUND: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin. METHODS: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] > or = 130 mg/dL [3.37 mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10 mg plus ezetimibe 10 mg (n = 12); rosuvastatin 10 mg plus placebo (matching ezetimibe 10 mg) (n = 12); ezetimibe 10 mg plus placebo (matching ezetimibe 10 mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10 mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) assay methods. RESULTS: All active treatments caused statistically significant (p < or = 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly (p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly (p < 0.01) greater percentage reduction in mean LDL-C (-61.4%) than rosuvastatin alone (-44.9%), with a mean incremental reduction of -16.4% (95%CI -26.3 to -6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin. CONCLUSIONS: Co-administration of ezetimibe 10 mg with rosuvastatin 10 mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.

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.

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. The pharmacokinetics of DM, dextrorphan (DX; the major DM metabolite), dacomitinib and PF-05199265 (an active metabolite of dacomitinib) were calculated. RESULTS: When combined with dacomitinib, the ratio of adjusted geometric means (90% CI) of DM area under the concentration-time curve (AUC)(last) was 955% (90% CI: 560%, 1,630%) and maximum plasma concentration (C (max)) was 973% (90% CI: 590%, 1,606%), compared with DM alone. For dacomitinib plus DM, exposures were consistent with those in patients receiving single-dose dacomitinib. Terminal elimination half-life (t (1/2)) was 51.4 h. Mild and moderate treatment-related adverse events were reported. No HV withdrew from the study. CONCLUSIONS: Single-dose administration of dacomitinib plus DM was safe and well tolerated in HVs and resulted in a significant increase in systemic exposures of DM in extensive metabolizers. No effect was observed on the pharmacokinetics of dacomitinib. Drug-drug interaction may occur when dacomitinib is concomitantly administered with therapeutic agents metabolized by cytochrome P450 (CYP) 2D6. Administration of drugs which are highly dependent on CYP2D6 metabolism may require dose adjustment, or substitution with an alternative medication.