769P - Pharmacokinetic boosting of olaparib: An open-label, prospective, cross-over study

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 expenses. 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 randomized, cross-over, multicenter trial compared the PK of olaparib 300 mg twice daily (BID) followed by olaparib 100 mg BID boosted with the non-therapeutic CYP3A-inhibitor cobicistat 150 mg BID for 7 days, or vice versa, in patients treated with olaparib. Equivalence was defined as a geometric mean ratio (GMR) of area-under-the-curve over one dosing interval (AUC_0-12h) and 90% Confidence Interval (CI) within the no-effect boundaries of 0.57-1.25.

Results

Of 15 included patients, 12 were eligible for PK analysis. The AUC_0-12h increased with the boosted reduced dose with a GMR of 1.45 (90% CI 1.27-1.65). The maximum plasma concentration was comparable (GMR 0.97; 90%CI 0.84-1.12), and the trough plasma concentration increased (GMR 4.14; 90%CI 3.25-5.27). PK parameters of both therapies are shown in the table. No grade ≥3 adverse events were reported during the study. Table: 769P

Pharmacokinetic parameters of the standard monotherapy and boosted therapy of olaparib. Data are represented as geometric mean (CV%) [confidence interval]

Conclusions

Boosting a 100 mg olaparib dose with the strong CYP3A-inhibitor cobicistat increases olaparib exposure with 45%, compared to the standard dose of 300 mg. Boosting of olaparib is therefore a promising strategy to reduce the olaparib dose. These results encourage a prospective study of boosted olaparib with toxicity-guided dose reductions. If adequate tolerability is established, boosting can lead to a substantial reduction in olaparib therapy costs. Drs. N.A.D. Guchelaar and M.I. Mohmaed Ali have equally contributed to the study.

Clinical trial identification

NCT05078671.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

ZonMw , The Netherlands Organization for Health Research and Development, as part of the Goed Gebruik Geneesmiddelen program (grant 10140021910005).

Disclosure

R.H. Mathijssen: Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis; Financial Interests, Institutional, Coordinating PI: Pamgene. I. Boere: Financial Interests, Institutional, Research Funding: GSK. P. Hamberg: Financial Interests, Personal, Advisory Board: Astellas, MSD, Pfizer, AstraZeneca, BMS, Ipsen. G.S. Sonke: Financial Interests, Research Funding: Merck, Agendia, AstraZeneca, Roche, Novartis; Financial Interests, Speaker, Consultant, Advisor: Novartis, Seattle Genetics, Biovica. N.P. Van Erp: Financial Interests, Institutional, Invited Speaker: Wad'n Workshop; Financial Interests, Institutional, Coordinating PI, IDS: Ipsen, Astellas. All other authors have declared no conflicts of interest.