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

Area of Science:

• Pharmacology
• Clinical Pharmacy
• Drug Interactions

Background:

• Pharmacokinetic (PK) boosting intentionally uses drug-drug interactions to increase drug exposure.
• Boosting olaparib, a CYP3A substrate, may reduce variability and cost.
• This study evaluated the equivalence of a boosted, lower olaparib dose versus the standard dose.

Purpose of the Study:

• To investigate the pharmacokinetic equivalence of a reduced, boosted dose of olaparib compared to the standard dose.
• To assess the efficacy of cobicistat as a pharmacokinetic booster for olaparib.

Main Methods:

• A cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted by cobicistat 150 mg BID.
• Patients received standard and boosted therapies sequentially, with PK sampling after seven days.
• Equivalence was defined by the 90% CI of the geometric mean ratio (GMR) for AUC0-12h, with boundaries set at 0.57-1.25.

Main Results:

• Twelve of 15 patients completed PK analysis.
• The GMR for AUC0-12h was 1.45 (90% CI 1.27-1.65), indicating a 45% increase in exposure.
• No grade ≥3 adverse events were reported.

Conclusions:

• Boosting olaparib 100 mg BID with cobicistat increased exposure 1.45-fold compared to the standard 300 mg BID dose.
• Dose equivalence was not established.
• Boosting is a potential strategy for dose reduction, but tolerability at higher exposures requires further investigation.