AbstractPexidartinib is an oral small‐molecule tyrosine kinase inhibitor that selectively targets colony‐stimulating factor 1 receptor. Two phase 1 single‐center trials were conducted in healthy subjects to determine the absorption, distribution, metabolism, and excretion of pexidartinib using radiolabeled drug and to assess the dose proportionality of pexidartinib following single oral doses. In the mass balance study, eight male subjects received a single oral dose of [14C]‐pexidartinib 400 mg with radioactivity assessed in plasma, urine, and feces samples taken at various timepoints postdose. In the dose‐proportionality study, 18 subjects received single doses of pexidartinib 200, 400, and 600 mg using randomization sequences. Peak pexidartinib and total radioactivity were observed at 1.75–2.0 hours after the oral dose and then declined in a multiphasic manner. The overall mean recovery of administered radioactivity was 92.2% over 240 hours with 64.8% in the feces and 27.4% in the urine. Major components detected in plasma were pexidartinib and glucuronide (M5, ZAAD‐1006a), with M5 and pexidartinib detected in urine and feces, respectively. A glucuronide of dealkylated form (M1) in the urine and multiple oxidized forms (M2, M3, and M4) in feces were detected. The dose‐proportionality study found dose‐proportional drug exposure between the 200‐ and 400‐mg doses and slightly less than proportional exposure between the 400‐ and 600‐mg doses. These results from these studies provide insight into pexidartinib disposition after oral administration and support the development of dosing guidance in subjects with renal or hepatic impairment or subjects taking cytochrome P450 3A and uridine disphosphate‐glucuronosyl transferase inhibitors and inducers.