Abstract 4508: Nonclinical pharmacokinetics of TAK-441, a hedgehog pathway inhibitor
| العنوان: | Abstract 4508: Nonclinical pharmacokinetics of TAK-441, a hedgehog pathway inhibitor |
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| المؤلفون: | Satoru Asahi, Junzo Takahashi, Hitomi Yamasaki, Kimio Tohyama, Lawrence Cohen, Toshiyuki Takeuchi, Mitsuhiro Nishihara, Yoshihiko Tagawa |
| المصدر: | Cancer Research. 71:4508-4508 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Cancer Research, medicine.medical_specialty, CYP3A4, Chemistry, Cmax, CYP1A2, Pharmacology, Bioavailability, Excretion, Endocrinology, Oncology, Pharmacokinetics, Oral administration, Internal medicine, medicine, ADME |
| الوصف: | TAK-441 is a potent and selective smoothened (Smo) antagonist that blocks hedgehog (Hh) signaling. TAK-441 is being developed for the treatment of advanced nonhematologic and hematologic malignancies. In vivo pharmacokinetic (PK) studies using rats and dogs and various in vitro studies were conducted to describe the PK of TAK-441 to support its clinical development. After oral administration of TAK-441 and/or [14C]TAK-441 to rats and dogs, plasma, urine, feces and bile were collected at designated time points. The concentrations of TAK-441 and total radioactivity in the biological samples were measured by high performance liquid chromatography / tandem mass spectrometry and liquid scintillation counter, respectively. The PK of TAK-441 was characterized in rats and dogs by low plasma clearance (397.9 and 161.3 mL/hr/kg), moderate plasma volume of distribution at steady state (681.6 and 2181.3 mL/kg), a moderate terminal elimination half-life (t1/2) (1.7 and 9.8 hours), and an oral bioavailability of 31.7% and 90.3%, respectively. A potential food effect was observed in dogs with an approximate 2-fold increase in the extent of absorption when TAK-441 was dosed to fed dogs (compared with fasted dogs), producing both a higher maximal drug concentration (Cmax) and area under the plasma concentration versus time curve from 0 to 24 hours (AUC0-24h). At 1 μg/mL, TAK-441 had high plasma protein binding in mice (99.7%) and rats (96.2%) and had lower plasma protein binding in dogs (79.6%) and humans (87.7%). No metabolites unique to humans were detected after incubation in hepatic microsomes. CYP3A4/5 was the major CYP isozyme contributing to the metabolism of TAK-441, followed by CYP2C19 and 2C9. The rank order of contribution of the five major human CYP isozymes to TAK-441 metabolism (determined using chemical inhibitors) was 3A4/5 (80.3%) >2C19 (14.4%) >2C9 (5.2%) >1A2 and 2D6 ( TAK-441 was mainly excreted in the feces as metabolites. Urinary excretion of the parent TAK-441 was quite low (LOQ and TAK-441 has high permeability in Caco-2 cells, is a poor substrate for efflux pump P-glycoprotein (P-gp), and is a weak inhibitor of P-gp (IC50 of 6.59 μM). In conclusion, TAK-441 has a favourable nonclinical absorption, distribution, metabolism, and excretion (ADME) profile for clinical evaluation and development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4508. doi:10.1158/1538-7445.AM2011-4508 |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::8ecace2c7a26a4522628772625629eb7 https://doi.org/10.1158/1538-7445.am2011-4508 |
| رقم الأكسشن: | edsair.doi...........8ecace2c7a26a4522628772625629eb7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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