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Efficacy and Safety Exposure‐Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients
Author(s) -
Zhou Diansong,
Li Jianguo,
Learoyd Maria,
Bui Khanh,
Berges Alienor,
Milenkova Tsveta,
AlHuniti Nidal,
Tomkinson Helen,
Xu Hongmei
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1338
Subject(s) - olaparib , medicine , hazard ratio , breast cancer , oncology , brca mutation , population , parp inhibitor , proportional hazards model , confidence interval , cancer , poly adp ribose polymerase , biology , biochemistry , environmental health , polymerase , gene
Olaparib is a poly ADP‐ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure‐response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/ II / III clinical studies from both capsule and tablet formulations were combined for efficacy ( N = 410) and safety ( N = 757) analyses. Exposure‐progression‐free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure‐safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer ( BRCA ) mutation status.