Tanya Boutros

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.

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 CT208: Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Dacomitinib (D) is a highly selective, irreversible small molecule inhibitor of the human epidermal growth factor receptor family of tyrosine kinases in clinical development for the treatment of non-small cell lung cancer (NSCLC). A 45-mg once daily oral dose is currently being evaluated in Phase 3 for NSCLC therapy in multiple settings. D has not previously been administered clinically as an intravenous dose. The absolute bioavailability (F%) of D in rats, dogs and monkeys was found to range from 56% to 100% at doses between 20 and 50 mg/kg. The current study was conducted to estimate the absolute bioavailability of D after oral administration (Test) relative to intravenous (IV, Reference) administration. Methods: A total of 14 healthy volunteers (HV) were enrolled in this Phase 1, open-label, 2-period, 2-treatment, fixed sequence study. Each HV received 2 treatments of D: Reference (20 mg IV infusion over 1 hour) and Test (45 mg oral), with a washout period of at least 16 days between each. Plasma samples to determine concentrations of D and its metabolite, PF-05199265, were collected at intervals up to 216 hours post-dose after IV or oral dose, and safety was assessed. F% was estimated as the ratio of dose-normalized adjusted geometric means of AUCinf for oral D and IV D using a mixed-effect model with treatment as a fixed effect and subject as a random effect. Corresponding 90% confidence intervals (CIs) were to be obtained from the same model. Results: The mean AUCinf, Cmax and CL/F for D after a single 45-mg oral dose were 1487 ng*hr/mL, 19.84 ng/mL and 30.27 L/hr, respectively. The mean AUCinf, Cmax and CL for D after a single 20-mg IV dose were 847 ng*hr/mL, 52 ng/mL and 23.61 L/hr, respectively. Mean pharmacokinetic parameters following a single oral dose in this study were similar to those observed in other single oral dose studies in HV. Conclusions: Assuming that clearance of D is similar via oral or IV administration at the administered doses, the absolute bioavailability of D was estimated to be 80.01% (90% CI: 74.90%, 85.47%). Single oral doses of D in both treatments were generally safe and well tolerated in the HV evaluated in this study. Citation Format: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello. Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT208. doi:10.1158/1538-7445.AM2014-CT208

Abstract LB-229: A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers

Introduction: Tamoxifen and one of its primary active metabolites, 4‑hydroxy‑tamoxifen, are known to induce CYP3A4 in vitro, and in vivo coadministration of tamoxifen with letrozole and anastrozole (both CYP3A4 substrates) has resulted in decreased exposures (AUC) of each by 37% and 27%, respectively. The primary route of oxidative metabolism of palbociclib (PD‑0332991) is through CYP3A4, thus coadministration of tamoxifen and palbociclib could result in decreased exposure of palbociclib. The primary objective of this study is to estimate the relative exposure of single 125 mg palbociclib oral doses alone and in the presence of steady‑state concentrations of tamoxifen and its active metabolites (4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen (N‑desmethyl‑4-hydroxytamoxifen)) in healthy male subjects in order to inform appropriate palbociclib dosing when administered in combination with tamoxifen in the upcoming Phase 3 PENELOPEB study. Methods: This was an open label, 2‑period fixed‑sequence study of the effect of multiple oral doses of tamoxifen on palbociclib pharmacokinetics in 25 healthy male volunteers. Each subject received a single 125 mg oral dose of palbociclib alone, followed by a single 125 mg dose of palbociclib on Day 22 of a 27-day tamoxifen loading dose regimen (60mg QD for 4 days, followed by 20mg QD for 23 days). Serial blood sampling for palbociclib pharmacokinetics was performed up to 144 hours post-palbociclib dose in both periods. Tamoxifen pre-dose blood sampling was performed on specified visits to document achievement of steady-state tamoxifen and metabolite concentrations. Plasma concentrations of palbociclib, tamoxifen, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen were each measured using validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) methods. Palbociclib plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion: There were no significant changes in the palbociclib plasma PK parameters AUCinf (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) in the presence of steady-state tamoxifen when compared to palbociclib alone. Tamoxifen, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen all achieved steady-state prior to administration of palbociclib in period 2. In general, palbociclib and the combination of palbociclib and tamoxifen were well tolerated with no reported serious adverse events; 1 subject discontinued due to generalized itchiness which resolved with a single dose of fexofenadine. Citation Format: Justin T. Hoffman, Melissa O9Gorman, Cho-Ming Loi, Anna Plotka, Tanya Boutros, Leonid Kirkovsky, Corrado Gallo Stampino, Diane Wang. A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2014-LB-229

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