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.
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Paribs are generally well tolerated by patients, with few reported side effects.
“Notably, Paribs are in general well tolerated by patients with few reported side effects (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010).”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Bundred et al., 2013
During this study's time frame, no toxicity or genomic instability appeared in MRL-45696-treated mice.
“Within the time-frame of this study, and in line with findings in Parp-1−/− mice (Bai et al., 2011) and in patients treated with Olaparib (Audeh et al., 2010; Bundred et al., 2013; Tutt et al., 2010), no toxicity or genomic instability was seen in MRL-45696-treated mice.”
From Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle (2014) · cites this paper as Bundred et al., 2013
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- Authors
- Bundred, N., Gardovskis, J., Jaskiewicz, J., Eglitis, J., Paramonov, V., McCormack, P., Swaisland, H., Cavallin, M., Parry, T., Carmichael, J., & Dixon, J. M.
- Affiliations
- Wythenshawe Hospital (GB)
- AstraZeneca (United Kingdom) (GB)
- Western General Hospital (GB)
- Corresponding author
- Bundred, Nigel
- Venue
- Investigational New Drugs
- Published
- 2013-01-13
- Volume
- 31
- Issue
- 4
- Pages
- 949-958
- ISSN
- 0167-6997 (ISSN-L)
- 1573-0646
- OpenAlex
- W2061762018
- Cited by
- 89
- References
- 20
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 14 · 2014: 10 · 2013: 2
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Investigational New Drugs (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- olaparib, PARP inhibitors, breast cancer surgery, pharmacokinetics, pharmacodynamics, PARP1 inhibition, dose-finding, peripheral blood mononuclear cells, BRCA mutations, homologous recombination deficiency, drug exposure, tolerability
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Breast Neoplasms, Demography, Enzyme Inhibitors, Female, Humans, Middle Aged, Phthalazines, Piperazines, Elective Surgical Procedures
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