Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study)

Joanneke K. Overbeek*, Niels A.D. Guchelaar, Ma Ida Mohmaed Ali, Petronella B. Ottevanger, Haiko J. Bloemendal, Stijn L.W. Koolen, Ron H.J. Mathijssen, Ingrid A. Boere, Paul Hamberg, Alwin D.R. Huitema, Gabe S. Sonke, Frans L. Opdam, Rob ter Heine, Nielka P. van Erp

*Corresponding author for this work

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Abstract

Background: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. Methods: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. Results: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. Conclusions: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.

Original languageEnglish
Article number113346
Number of pages8
JournalEuropean Journal of Cancer
Volume194
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Cobicistat
  • CYP3A4
  • Olaparib
  • Pharmacoenhancement
  • Pharmacokinetic boosting

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