Grace Ni

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.

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. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2–7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1–3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed‐effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co‐administration and by 103% and 16%, respectively, with ketoconazole co‐administration. Tofacitinib half‐life increased by approximately 1 hour during co‐administration with fluconazole or ketoconazole. Co‐administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.

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.

Abstract 763: A phase 1 open-label study to investigate the potential drug-drug interaction (DDI) between single-dose (SD) dacomitinib (PF-00299804; DC) and steady-state (SS) paroxetine (PX) in healthy volunteers (HVs)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: DC, a small molecule, pan-HER inhibitor, is partly metabolized by cytochrome P450 (CYP) 2D6. Concomitant administration with therapeutic agents that are inhibitors of CYP2D6 could potentially cause DDIs. This study evaluated the effect of PX, a potent CYP2D6 inhibitor, on the pharmacokinetics (PK) of DC in HVs who were extensive CYP2D6 metabolizers. The safety and tolerability of SD DC was also assessed when given alone and co-administered with PX. Methods: In this Phase 1, single fixed-sequence, 2-period study, 14 HVs received a 45 mg SD of DC alone (Period 1). After a 21-day washout, 30 mg of PX was given daily for 10 days (Period 2) and on Day 4, a 45 mg SD of DC was co-administered with PX. Blood samples were collected up to 240 h post DC dose in both periods and analyzed for DC, its CYP2D6 metabolite PF-05199265, and PX using validated high performance liquid chromatographic tandem mass spectrometric methods. PK parameters were calculated using noncompartmental methods. Analysis of variance was performed on natural log transformed AUC and Cmax to estimate adjusted mean treatment differences and 90% confidence intervals (CI) which were exponentiated to produce the adjusted geometric mean ratio (GMR) and 90% CI of the ratios. Results: 14 males (median age 41 [23-54] yrs; 9 black, 5 Caucasian) were evaluated for PK and safety. The GMR and 90% CI of AUCinf and Cmax for DC when given as DC + PX vs DC alone was 137.2% (109.1%, 172.6%) and 110% (82.9%, 145.1%), respectively. Median Tmax of DC was 8 and 10 h post dose, and its half-life was 96 and 90 h, in the presence and absence of PX, respectively. Total exposure (AUC240) to PF-05199265 was decreased in the presence of SS PX (33.5 vs 322 ng.hr/mL). There were no serious adverse events (AEs), severe AEs, or deaths during the study. The majority of AEs were mild (including all 14 events reported during DC treatment alone) and resolved. Conclusions: PX inhibited DC metabolism resulting in 90% reduction in exposure (AUC240) of the CYP2D6 metabolite, PF-05199265. No meaningful change in absorption was observed when DC was given with SS concentrations of PX. DC seems to present a low extraction profile and high variability during the absorption phase, the latter probably due to its physicochemical characteristics (BCS Class II). In the presence of PX, there was an approximate 37% increase in DC exposure (AUCinf) with a wide CI, reflecting large intra-subject variability. The DC change in exposure reported in this study is likely to be less in the clinical setting (45 mg QD). As the exposure of DC reported in the presence of PX is within the range shown to be tolerated and efficacious, no dose adjustment is recommended for DC when administered concomitantly with a CYP2D6 inhibitor, such as PX. SD DC administered alone and in combination with PX was well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 763. doi:1538-7445.AM2012-763

Abstract 2762: An open-label phase 1 study to evaluate the pharmacokinetics of axitinib (AG-013736) in healthy Chinese volunteers

Introduction: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is mainly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP1A2, CYP2C19, and uridine glucuronyltransferase (UGT1A1). Axitinib currently is in Phase 3 development for renal cell carcinoma. As part of the global clinical development program for axitinib, studies are ongoing in cancer patients in China. A clinical assessment of axitinib pharmacokinetics in healthy Chinese subjects, including dose-proportionality, was conducted to support the regulatory submission in China. Methods: This was an open-label, fixed-sequence study conducted in mainland China in 14 healthy volunteers. All subjects received a single axitinib dose of 5 mg, 7 mg, and 10 mg under fed conditions in study periods 1, 2, and 3, respectively, followed by safety and pharmacokinetic monitoring. Each study period was separated by a washout period of at least 7 days between successive axitinib doses. Serial blood sampling for axitinib pharmacokinetics was performed up to 32 hours postdose in each period. Plasma concentrations of axitinib were measured using a validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) method. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Results: Axitinib AUC 0-∞ (area under the curve from time zero to infinity) and C max (maximal plasma concentration) estimates in healthy Chinese volunteers in this study are reported here. The geometric mean estimate of AUC 0-∞ was 150, 251, and 321 ng[[Unable to Display Character: ∙]]h/mL for doses of 5 mg, 7 mg, and 10 mg, respectively. This represented AUC 0-∞ increments of 1:1.7:2.1 for dose increments of 1:1.4:2, respectively (ie, a proportional increase in AUC 0-∞ per dose increment). Similarly, the geometric mean estimate of C max was 33.5, 51.1, and 69.4 ng/mL for 5 mg, 7 mg, and 10 mg, respectively, representing C max increments of 1:1.5:2.1 for dose increments of 1:1.4:2, respectively (a proportional increase in C max per dose increment). Axitinib was well tolerated with no serious adverse events (AEs) or discontinuations; the only observed AE was mild abdominal distension in 1 subject. Conclusions:. Dose-proportional linear pharmacokinetics for axitinib were observed for the 5 mg to 10 mg dose range in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2762.