An Open-Label, Sequential-Design Drug Interaction Study of the Effects of Omeprazole on the Pharmacokinetics of Ibrutinib in Healthy Adults

Abstract

Background: Ibrutinib, a potent irreversible inhibitor of Bruton’s tyrosine kinase, is approved for the treatment of patients with mantle cell lymphoma (who have failed at least one prior therapy), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; including patients with 17p deletion), or Waldenström’s macroglobulinemia. Ibrutinib exhibits pH-dependent solubility (insoluble at pH ≥ 3); therefore, pH-altering agents that increase gastric pH may have the potential to impact the pharmacokinetics (PK) of ibrutinib. Physiologically-based PK modeling and simulation suggested that an increase in gastric pH would minimally impact the bioavailability of ibrutinib. To evaluate potential drug interactions between ibrutinib and pH-altering agents, a phase 1 clinical study of the effect of omeprazole, a proton pump inhibitor (PPI), on the PK of ibrutinib in healthy adults was conducted.Methods: An open-label, sequential-design drug interaction study of omeprazole coadministered with ibrutinib was conducted in healthy adults (18-55 years, inclusive). Key inclusion criteria included healthy men and women of non-childbearing potential, body mass index between 18 and 30 kg/m2, inclusive, and body weight ≥ 50 kg. On day 1, a single dose of ibrutinib (560 mg) was administered alone after an overnight fast. On days 3-6, omeprazole (40 mg) was administered alone 1 hr before breakfast. On day 7, omeprazole was administered after an overnight fast, and a single dose of ibrutinib was administered 2 hr after the omeprazole dose. Water was allowed ad libitum beginning 2 hr after ibrutinib dosing, and lunch was served ~4 hr after ibrutinib dosing.Serial PK blood samples were collected over 48 hr following dosing on days 1 and 7. Key PK parameters for ibrutinib and its metabolite (PCI-45227) were summarized for each treatment. The effect of omeprazole was determined by assessing geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC). Safety and tolerability were evaluated throughout the study.Results:Twenty healthy adults (95% men) completed the study; the median age was 48 yr and median body mass index was 25.8 kg/m2. The mean plasma concentration-time profile for ibrutinib is presented in Figures 1 and 2. AUC up to the last measurable concentration (AUClast) was similar for ibrutinib alone and in combination with omeprazole (GMR [90% CI] = 92.5%; [66.5 - 128.7]). Similar results were observed for AUC from time 0 to 48 hr (AUC48hr).Cmax of ibrutinib alone was higher than that observed when ibrutinib was coadministered with omeprazole (39.5 vs. 14.8 ng/mL, respectively; GMR (90% CI) = 37.5% (25.1 - 56.0). Median time to maximum concentration (tmax) was longer with ibrutinib plus omeprazole (2.0 hr) than with ibrutinib alone (1.0 hr). A similar reduction in Cmax and delay in tmax was observed for PCI-45227; mean AUC of PCI-45227 was approximately 20% higher when ibrutinib was administered alone than when coadministered with omeprazole.Whereas Cmax values were lower when ibrutinib was coadministered with omeprazole, the mean effect of omeprazole on AUC was minimal (<10%), albeit with a large CI. The AUC results were consistent with a population PK analysis which demonstrated that with the exception of a longer duration of absorption, coadministration of ibrutinib and antacids (mainly PPIs) under non-fasted conditions had no effect on PK parameters (Marostica E et al., Cancer Chemother Pharmacol 2015; 75:111-121). It should be noted that the effect of omeprazole coadministration on ibrutinib Cmax may be less pronounced under non-fasted conditions: because food intake itself increases gastric pH, dissolution and/or precipitation of ibrutinib in the stomach and intestinal tract would be similar for test and reference treatments.The most commonly reported treatment-emergent adverse events (AEs) were back pain (3/20; 15%), headache (2/20; 10%), abdominal pain (2/20; 10%), and diarrhea (2/20; 10%), which were all grade 1 in severity. No serious AEs were reported.Conclusions: Coadministration of omeprazole with ibrutinib decreased Cmax while marginally affecting AUC in healthy adults. Because AUC is deemed most relevant for ibrutinib's activity, coadministration of PPIs and other pH-altering agents with ibrutinib is not considered to have a clinically relevant effect on ibrutinib exposure. [Display omitted] [Display omitted] Disclosuresde Jong:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. Jiao:Janssen: Employment. Sukbuntherng:Pharmacyclics, LLC: Employment, Equity Ownership; Global Blood Therapeutics: Equity Ownership. Ouellet:Janssen: Employment.