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Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

Authors :
Maud Velev
Alicja Puszkiel
Benoit Blanchet
Sixtine de Percin
Nicolas Delanoy
Jacques Medioni
Claire Gervais
David Balakirouchenane
Nihel Khoudour
Patricia Pautier
Alexandra Leary
Zahra Ajgal
Laure Hirsch
François Goldwasser
Jerome Alexandre
Guillaume Beinse
Source :
Pharmaceuticals, Vol 14, Iss 8, p 804 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

Details

Language :
English
ISSN :
14248247
Volume :
14
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.58923e84ca98466e86ca7b10c494bf84
Document Type :
article
Full Text :
https://doi.org/10.3390/ph14080804