Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects

Abstract

This study investigated the pharmacokinetics, excretion, and metabolism of pamapimod following a single oral dose in healthy male subjects. Nonradio-labeled pamapimod was supplied as bulk powder, [14C]-labeled pamapimod was supplied as ethanol solution. Pamapimod, metabolic synthetic standards, and the internal standard were supplied by Roche. This was an open-label, singledose mass balance study. Healthy male subjects received a single oral dose of 300 mg [14C]-labeled pamapimod. Quantification of pamapimod and metabolites was determined by a validated liquid chromatography/tandem mass spectrometry method (LC/MS/ MS). Urine, blood, and feces were collected for metabolic profiling and radioactivity analysis. Profiling was done using high performance liquid chromatography (HPLC)/ LC/MS/MS. Radioactivity determination was by liquid scintillation counting. Six subjects completed the study. Mean Cmax was 4,120 ng/ml at tmax of 2.8 h, and mean AUCinf was 19,800 ng·h/ml. The t1/2 of pamapimod was 7.2 h. Mean drug recovery was 100 ± 2% by 120 h, of which 76.5% was recovered in urine and 23.9% in feces. Unchanged pamapimod accounted for 15.3% excreta, indicating metabolism is the major elimination pathway. Five metabolites were identified in plasma, urine, and feces. In urine, 41.1% of the dose was excreted as carboxylate metabolite (RO4498496), 19.2% as lactol metabolite (RO4493992), and 12.5% as pamapimod. In feces, 18.5% was excreted as RO4498496, 2.8% as pamapimod. The majority of dose was renally cleared. Urinary and fecal metabolites accounted for > 80% radioactivity. These results indicate hepatic metabolism followed by renal excretion is the major elimination pathway of pamapimod.