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Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.
Cancer Chemother Pharmacol ; 76(3): 587-95, 2015 Sep.
Article em En | MEDLINE | ID: mdl-26210682
PURPOSE: RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. METHOD: In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. RESULTS: With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. CONCLUSION: Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imidazolinas / Proteínas Proto-Oncogênicas c-mdm2 / Neoplasias Tipo de estudo: Clinical_trials Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Imidazolinas / Proteínas Proto-Oncogênicas c-mdm2 / Neoplasias Tipo de estudo: Clinical_trials Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article