12 research outputs found
Safety and Efficacy of Dacomitinib in Korean Patients with KRAS Wild-Type Advanced Non–Small-Cell Lung Cancer Refractory to Chemotherapy and Erlotinib or Gefitinib: A Phase I/II Trial
IntroductionDacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).MethodsThe phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).ResultsTwelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms “cough” and “pain” showed improvement within 3 weeks of initiating treatment.ConclusionsDacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor
Abcg2/Bcrp1 mediates the polarized transport of antiretroviral nucleosides abacavir and zidovudine,” Drug Metabolism and Disposition: The Biological Fate of Chemicals
ABSTRACT: The bioavailability and targeted distribution of abacavir (ABC) and zidovudine (AZT) to viral reservoirs may be influenced by efflux transporters. The purpose of this study was to characterize the interaction of these nucleoside reverse transcriptase inhibitors with the Abcg2/Bcrp1 transporter, the murine homolog of human breast cancer resistance protein (BCRP), using a Bcrp1-trans
Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine
P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution. Drug Metab Dispos 2007; 35(11):2076–2085
Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6
P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution
Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design
In vitro assays are frequently used for the screening of substrates and
inhibitors of transporter-mediated efflux. Examining directional flux across
Madin-Darby canine kidney (MDCK) II cell monolayers that overexpress a
transporter protein is particularly useful in identifying whether or not a
candidate compound is an inhibitor or substrate for that transport system.
Studies that use a single substrate or inhibitor in competition assays can be
challenging to interpret because of the possible multiple mechanisms involved
in substrate/inhibitor-protein interactions. During our previous studies of
substrate-inhibitor-transporter interactions, we observed differences in
breast cancer resistance protein (BCRP) inhibition, depending on the substrate
and the inhibitor. Therefore, we investigated BCRP-mediated interactions with
a 4 × 4 matrix of substrates and inhibitors using monolayers formed from
MDCKII cells transfected with murine BCRP (Bcrp1/Abcg2). The selective BCRP
inhibitor
3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino
[1′,2′:1,6] pyrido [3,4-b]indol-3-yl)-propionic acid
tert-butyl ester (Ko143) effectively inhibited the Bcrp1-mediated
transport of all substrates examined. However,
N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine
carboxamide (GF120918), nelfinavir, and Pluronic P85 exhibited differences in
inhibition depending on the substrate examined. Our findings support recent
reports suggesting that the interactions of substrate molecules with BCRP
involve multiple binding regions in the protein. The nucleoside substrates
zidovudine and abacavir seem to bind to a region on BCRP that may have little
or no overlap with the binding regions of either prazosin or imatinib. In
conclusion, the choice of substrate or inhibitor molecules for an in vitro
assay system can be crucial for the optimal design of experiments to evaluate
transporter-mediated drug-drug interactions
Prophylactic doxycycline (doxy) lessens rash from dacomitinib (D) an EGFR inhibitor with no rash or diarrhea improvement from corticosteroids or probiotics.
Impact of a planned dose interruption of dacomitinib in the treatment of advanced non-small-cell lung cancer (ARCHER 1042)
Objectives: Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. Materials and methods: Patients, treatment-nave for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45 mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14. The primary endpoint was the pharmacokinetic (PK) characteristics of dacomitinib in Cycle 1 Day 10 and during dose interruption. Secondary endpoints included safety and concomitant medications used to treat AEs of interest. Results: Cohort III enrolled 25 patients. Median plasma C-max of dacomitinib in Cycle 1 Day 10 was 83.40 ng/mL. Average median plasma dacomitinib concentration during the 4-day dose interruption was 42.63 ng/mL. In the first 8 weeks of treatment 1)80% of patients used concomitant medications for derma-tologic AEs, 76% for diarrhea, and 44% for stomatitis, and 2) all patients experienced treatment-emergent AEs and 28% had all-causality Grade 3 AEs. Conclusion: At 45 mg QD dosing, PK parameters of plasma dacomitinib in Cycle 1 Day 10 were comparable to that obtained in Cycle 1 Day 14 from other dacomitinib studies. Average median plasma dacomitinib concentration during the 4-day dose interruption was approximately half of the median plasma Cmax of dacomitinib observed prior to dose interruption. The toxicity profile was consistent with that from other studies of dacomitinib. (C) 2017 Elsevier B.V. All rights reserved.