Abstract 2043: Effects of 24-h carboplatin pretreatment on olaparib clearance in women's cancers using noncompartmental and population pharmacokinetic analyses
Authors: Goey Andrew K.L. , Peer Cody J. , Sissung Tristan M. , Roth Jeffrey , Shahbazi Shandiz , Nguyen Jeffers , Annunziata Christina M. , Houston Nicole , Kohn Elise C. , Lee Jung-Min , Figg William D. 
Published: July 2016

Abstract
Background: Olaparib (OLA) is a PARP inhibitor approved for use in deleterious germline BRCA mutated recurrent or refractory ovarian cancer. Combining OLA with carboplatin (CARBO) could have additive effects based on platinum-DNA adducts requiring PARP for DNA repair. Preclinical data suggest greater cytotoxicity when CARBO is given prior to OLA. However, the optimal treatment sequence of these agents has not been studied previously in patients. We therefore investigated: 1) the effects of CARBO treatment on the pharmacokinetics (PK) and pharmacodynamics (PD) of OLA; 2) in vitro mechanisms of the interaction between CARBO and OLA.
Methods: Clinical PK and PD data of OLA were obtained from 58 patients with confirmed recurrent or refractory women's cancers participating in a two arm, parallel design, phase 1 trial (NCT01237067). In cycle 1 OLA tablets (200 mg BID) were given for 7 days either followed by CARBO (AUC 4) on day 8 (arm A) or after CARBO on day 1 (Arm B). In cycle 2 the arms received the reversed scheme. PK of OLA were assessed in both cycles by noncompartmental (NCA) and population pharmacokinetic (PPK) analyses. For PK/PD analyses, PAR levels were measured at baseline and 24 h after the first OLA dose. In vitro mechanistic studies were carried out by incubating whole human blood and avian DT40 PARP-1 KO cells with 10 μM CARBO for 24 h, followed by 1h-treatment of isolated PBMCs and PARP-1 KO cells with 10 μM OLA. Intracellular OLA concentrations were determined using UPLC-MS/MS.
Results: Both NCA and PPK analyses showed a ∼50% increase in OLA clearance when CARBO was administered 24-h prior (P&lt;0.02). The PPK model included a lag time parameter (P = 1.1E-18), a second absorption compartment (P = 7.7E-27), a single elimination compartment, and accounted for covariance among the clearance and volume parameters (P = 6.7E-7). Presence of CARBO was the only significant covariate affecting OLA clearance (P = 1.9E-13). Final estimates for clearance and volume of distribution were 6.8 L/h and 33 L, respectively, which were comparable with related reports. There were no trends between PK data and PAR levels, nor did the presence of CARBO affect PAR levels (P = 0.89). PBMC experiments showed that 24-h pretreatment with CARBO significantly increased intracellular OLA concentrations by more than 30% compared with control samples (P = 0.013). PARP-1 KO cells confirmed that intracellular PARP expression was not related to the increased OLA uptake. Possibly, CARBO affects other intracellular targets or transporters leading to increased intracellular uptake of OLA from the bloodstream.
Conclusion: This is the first known PK analysis showing a significant increase in OLA clearance after pretreatment with CARBO, possibly leading to subtherapeutic plasma concentrations of OLA. Preclinical experiments are ongoing to reveal the exact pharmacological mechanisms of this interaction.
Citation Format: Andrew K.L. Goey, Cody J. Peer, Tristan M. Sissung, Jeffrey Roth, Shandiz Shahbazi, Jeffers Nguyen, Christina M. Annunziata, Nicole Houston, Elise C. Kohn, Jung-Min Lee, William D. Figg. Effects of 24-h carboplatin pretreatment on olaparib clearance in women's cancers using noncompartmental and population pharmacokinetic analyses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2043.