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 Cmax and a modest increase (31%) in 
AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 
metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC 
were both 45% higher for the SDP formulation. While the low-fat meal caused a 
less than 20% increase in all PK exposure parameters with the 90% CI values just 
outside the upper end of the equivalence criteria (80-125%), the high-fat meal 
reached bioequivalence with dosing under fasting.
CONCLUSION: 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.