The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure

• Published in: Cancer chemotherapy and pharmacology Vol. 82; no. 2; pp. 299 - 308
• Main Authors: de Jong, Jan, Haddish-Berhane, Nahor, Hellemans, Peter, Jiao, James, Sukbuntherng, Juthamas, Ouellet, Daniele
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2018; Springer Nature B.V
• Subjects: Adult; Bioavailability; Cancer Research; Chemotherapy; Drug dosages; Drug Interactions; Female; Humans; Hydrogen-Ion Concentration - drug effects; Inhibitor drugs; Lymphoma; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Omeprazole; Omeprazole - adverse effects; Omeprazole - blood; Omeprazole - pharmacology; Oncology; Oral administration; Original Article; pH effects; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Proton pump inhibitors; Proton Pump Inhibitors - blood; Proton Pump Inhibitors - pharmacology; Pyrazoles - adverse effects; Pyrazoles - blood; Pyrazoles - pharmacokinetics; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; R&D; Research & development; Targeted cancer therapy; Drug interaction; pH-altering agents; Pharmacokinetics; Proton-pump inhibitors; Ibrutinib
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-018-3613-9

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 AUC 48h and AUC last 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); C max decreased by 62.5% (GMR [90% CI] 37.5% [26.4–53.4]), with delayed t max (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 C max on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study. Conclusions The decrease in C max 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.