Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide.

The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open-label, randomized clinical studies. The presence of a drug interaction was concluded if the 90% confidence intervals for the geometric least squares mean ratios of AUC(0-t) (AUC(0-48) for levothyroxine) and C(max) fell outside the no-effect limits of (80.0%, 125.0%). Concomitant administration of colesevelam had no effect on the AUC(0-t) or C(max) of pioglitazone but significantly decreased the AUC(0-t) and C(max) of glyburide, levothyroxine, and EE and the C(max) of repaglinide and NET. AUC(0-t) and C(max) of glyburide and EE, but not repaglinide or NET, were significantly decreased when the drug was given 1 hour before colesevelam. When glyburide, EE, or levothyroxine was given 4 hours before colesevelam, no drug interaction was observed. Although colesevelam has a cleaner drug interaction profile than other bile acid sequestrants, it does interfere with absorption of some drugs. A 4-hour window appears sufficient to eliminate these interactions.