A phase I study was conducted to assess the metabolism and excretion of [ 14 C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 mCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-highperformance liquid chromatography-tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy-and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned a to an alkyl (ethyl or t-butyl) side chain.
1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.
Cl renal,iv ; renal clearance; Cl h,iv,blood , hepatic blood clearance; C max , maximum observed plasma concentration; CVb, between participant variability; CYP, cytochrome P450; DDI, drug-drug interaction; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; E h , hepatic extraction ratio; F, absolute oral bioavailability; fa, fraction of linerixibat absorbed; fg, fraction escaping first-pass gut metabolism; F h , first pass liver extraction; GI, gastrointestinal; IBAT, ileal bile acid transporter; IC 50 , half maximal inhibitory concentration; ICRP, International Commission on Radiological Protection; IV, intravenous; IVIVE, in vitro-to-in vivo extrapolation; LC-MS/MS, liquid chromatography with tandem mass spectrometry; LLQ, lower limit of quantification; LSC, liquid scintillation counting; PBC, primary biliary cholangitis; PK, pharmacokinetics; QC, quality control; Qh, hepatic blood flow; SD, standard deviation; t 1/2 , half-life; V ss , volume of distribution; V z , terminal volume
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