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Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

ABSTRACT: PURPOSE:To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated. METHODS:Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [14C]regorafenib. Plasma concentrations of parent drug were derived from HPLC-MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [14C]regorafenib was incubated with human hepatocytes and analyzed using HPLC-LSC and HPLC-HRMS/MS. RESULTS:Regorafenib was the major component in plasma, while metabolite M-2 (pyridine N-oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N-oxide) and M-7 (N-glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1-4 h and again at 6-24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation. CONCLUSIONS:Regorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug-drug interactions.

SUBMITTER: Gerisch M

PROVIDER: S-EPMC5754413 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

Gerisch Michael M Hafner Frank-Thorsten FT Lang Dieter D Radtke Martin M Diefenbach Konstanze K Cleton Adriaan A Lettieri John J

Cancer chemotherapy and pharmacology 20171129 1

<h4>Purpose</h4>To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated.<h4>Methods</h4>Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [<sup>14</sup>C]regorafenib. Plasma concentrations of parent drug were derived from HPLC-MS/MS analysis and total radioactivity from liqui ...[more]

PMID: 29188322

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Project description:AimsTo characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men.MethodsDouble-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated.ResultsIn total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study.ConclusionsExposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.

Dataset Information

Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

Publications

Mass balance, metabolic disposition, and pharmacokinetics of a single oral dose of regorafenib in healthy human subjects.

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