John Nemunaitis1, Annie Young2, Samuel Ejadi3, Wilson Miller4, Lin-Chi Chen5, Gwen Nichols5, Steven Blotner5, Faye Vazvaei5, Jianguo Zhi6, Albiruni Razak7. 1. Mary Crowley Cancer Research Center, Dallas, TX, USA. 2. Roche Innovation Center of Welwyn, Welwyn Garden City, UK. 3. Scottsdale Healthcare Hospitals DBA HonorHealth, Scottsdale, AZ, USA. 4. Jewish General Hospital/McGill University, Montreal, Canada. 5. Roche Innovation Center of New York, New York, NY, 10016, USA. 6. Roche Innovation Center of New York, New York, NY, 10016, USA. jianguo.zhi@roche.com. 7. Medical Oncology and Haematology, Princess Margaret Hospital, Toronto, Canada.
Abstract
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.
RCT Entities:
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.
Authors: Harry P Erba; Pamela S Becker; Paul J Shami; Michael R Grunwald; Donna L Flesher; Min Zhu; Erik Rasmussen; Haby A Henary; Abraham A Anderson; Eunice S Wang Journal: Blood Adv Date: 2019-07-09
Authors: W Larry Gluck; Mrinal M Gounder; Richard Frank; Ferry Eskens; Jean Yves Blay; Philippe A Cassier; Jean-Charles Soria; Sant Chawla; Vincent de Weger; Andrew J Wagner; David Siegel; Filip De Vos; Erik Rasmussen; Haby A Henary Journal: Invest New Drugs Date: 2019-07-29 Impact factor: 3.651