thiourea and Headache

Amuvatinib is a multi-targeted tyrosine kinase inhibitor with activity that also disrupts DNA damage repair through suppression of homologous recombination protein Rad51. Amuvatinib dry-powder capsules (DPC) showed evidence of activity in early Phase 1 cancer studies but low systemic exposure. The purposes of the studies were to investigate the cause of low exposure, develop, and test an alternative formulation with improved exposure, and establish the dose to be tested in future studies in cancer patients.. Three studies were conducted in a total of 58 healthy subjects: a food-effect study using amuvatinib DPC, a single-dose pharmacokinetic study comparing amuvatinib DPC to a new lipid-suspension capsules (LSC), and a multiple-dose pharmacokinetic study using amuvatinib LSC.. A high-fat meal administered with amuvatinib DPC increased the rate and extent of absorption compared to the Fasted state, a 183 and 118% increase in the mean C(max) and AUC(0-∞) of amuvatinib, respectively. The single-dose pharmacokinetics of amuvatinib LSC resulted in an approximately two-third-fold increased exposure (AUC) compared with amuvatinib DPC. The multiple-dose pharmacokinetics of the amuvatinib LSC 300 mg administered every 8 h exhibited improved accumulation compared with the 12-h regimens and achieved presumed therapeutic level safely with no serious or severe adverse events reported. No subject discontinued treatment due to an adverse event.. Amuvatinib LSC, 300 mg every 8 h, is being studied in cancer patients based on the improved exposure and similar safety profile to amuvatinib DPC. A lipid-based formulation approach may be a useful tool for other low aqueous soluble compounds.

Topics: Administration, Oral; Adult; Area Under Curve; Capsules; Cross-Over Studies; Dietary Fats; Fasting; Female; Food-Drug Interactions; Headache; Humans; Male; Metabolic Clearance Rate; Piperazines; Pyrimidines; Thiourea; Young Adult