rg7388 and posaconazole

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.. 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.. The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in C. In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.

Topics: Administration, Oral; Area Under Curve; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors; Drug Compounding; Drug Interactions; Fasting; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; para-Aminobenzoates; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Tablets; Therapeutic Equivalency; Triazoles