Peer Cody J, Lee Jung-Min, Roth Jeffrey, Rodgers Louis, Nguyen Jeffers, Annunziata Christina M, Minasian Lori, Kohn Elise C, Figg William D
Clinical Pharmacology Program, CCR, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room 5A01, Bethesda, MD, 20892, USA.
Women's Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Cancer Chemother Pharmacol. 2017 Jul;80(1):165-175. doi: 10.1007/s00280-017-3346-1. Epub 2017 Jun 2.
Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance.
To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters.
Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data.
Simulations predicted lower steady-state peak/trough olaparib exposure through 24-36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.
在最近的一项I/Ib期联合试验中，奥拉帕利与卡铂联合使用最近被证明在BRCA和非BRCA突变癌症中均具有活性。推荐的最佳用药顺序是在奥拉帕利前1天使用卡铂。然而，卡铂预处理使奥拉帕利的清除速度加快了约50%。
为了进一步探索这种药物相互作用，设计了一个群体药代动力学（PK）模型，该模型包括一个滞后时间参数、来自片剂制剂的第二个吸收室、一个单一的分布/消除室以及清除率和体积参数之间的协方差。
清除率（6.8 L/h）和体积（33 L）估计值与文献相当。唯一显著的协变量是卡铂的存在对奥拉帕利清除率的影响，这与已发表的非房室PK和体外数据一致。
模拟预测卡铂预处理后24 - 36小时内奥拉帕利的稳态峰谷暴露量较低，但这种效应在第2天就消失了，因此不建议调整剂量。
