Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors. Method This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low- energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability. Results The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in C and a modest increase (31%) in AUC for idasanutlin, a marked reduction in C (~ 60%) and AUC0 (~ 50%) max max for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. C and AUC were both 45% higher for the max SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90%
Cancer Chemotherapy and Pharmacology – Springer Journals
Published: Jan 24, 2018
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