title: Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.
abstract: Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.
authors: Department of Academic Surgery, Education and Research Centre, University Hospital of South Manchester, Wythenshawe, M23 9LT Manchester, UK. bundredn@manchester.ac.uk
authors: Nigel
authors: N
authors: Bundred
authors: Janis
authors: J
authors: Gardovskis
authors: Janusz
authors: J
authors: Jaskiewicz
authors: Janis
authors: J
authors: Eglitis
authors: Viktor
authors: V
authors: Paramonov
authors: Peter
authors: P
authors: McCormack
authors: Helen
authors: H
authors: Swaisland
authors: Maria
authors: M
authors: Cavallin
authors: Tony
authors: T
authors: Parry
authors: James
authors: J
authors: Carmichael
authors: J Michael
authors: JM
authors: Dixon
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D003710:Demography; D017558:Elective Surgical Procedures; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D010793:Phthalazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib