Published in:
01-08-2018 | Original Article
The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure
Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018
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Purpose
This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib’s pharmacokinetics (PK) in healthy participants.
Methods
This open-label, sequential-design study included 20 healthy adults aged 18–55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3–6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib’s PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model.
Results
AUC48h and AUClast of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1–116.3] and 92.5% [77.8–109.9], respectively); Cmax decreased by 62.5% (GMR [90% CI] 37.5% [26.4–53.4]), with delayed tmax (1−2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased Cmax on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study.
Conclusions
The decrease in Cmax without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib’s bioavailability. No dose adjustments are recommended during ibrutinib’s co-administration with omeprazole or other pH-altering agents.