A Drug-Drug Interaction Study of Ibrutinib with Moderate and Strong CYP3A Inhibitors in Patients with B-Cell Malignancy

Background:Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (including 17p deletion), and Waldenström's macroglobulinemia. Because ibrutinib is extensively cleared by cytochrome P450 (CYP) 3A4, concomitant treatment with CYP3A inhibitors has been shown to increase ibrutinib exposure in healthy adults. However, sparse PK data from uncontrolled phase 2 studies with moderate CYP3A inhibitors showed a lower magnitude of drug-drug interactions (DDI) than observed in studies with healthy subjects or in silico simulations under nonfasted conditions (data on file). This phase 1 study was conducted to evaluate potential DDIs between ibrutinib and CYP3A inhibitors in patients with B-cell malignancies and to confirm recommended dose adjustments.

Methods: This was an open-label, multicenter, DDI study of ibrutinib with erythromycin (moderate CYP3A inhibitor) and voriconazole (strong CYP3A inhibitor) in patients (≥ 18 years) with relapsed/refractory B-cell malignancy. During the first treatment cycle, patients received an oral dose of 560 mg ibrutinib on days 1-4 (steady-state) and days 14-18. On days 5-13 and 19-27, the dose was reduced to 140 mg ibrutinib and combined with erythromycin (500 mg tid on days 5-11) and then with voriconazole (200 mg bid on days 19-25). On PK sampling days (days 4 [alone], 11 [with erythromycin], and 25 [with voriconazole]), ibrutinib was administered 30 min before a standard breakfast. On these PK sampling days, the morning doses of voriconazole and erythromycin were administered 1 hr prior to ibrutinib and together with ibrutinib, respectively.

PK samples were taken pre- and up to 24 hr postdose; key PK parameters were summarized for ibrutinib, PCI-45227 (ibrutinib metabolite), erythromycin, and voriconazole. After completion of the DDI assessment during cycle 1, patients continued treatment with ibrutinib monotherapy at therapeutic doses. Safety was evaluated throughout the study.

Results:All patients (N = 26) completed the PK assessments in cycle 1; 54% were men, and the median age was 65 years. The geometric mean ratio (GMR) for dose-normalized maximum concentration (C_max) and area under the plasma concentration-time curve from time 0 to 24 hr (AUC_24h) for ibrutinib was 3.35 and 2.99, respectively, when given in combination with erythromycin (Table). When ibrutinib was coadministered with voriconazole, the GMR for C_max and AUC_24h was 6.71 and 5.74, respectively (Table). Four out of 26 patients showed either no interaction between ibrutinib and erythromycin or a lower ibrutinib exposure (AUC ratios 0.27-0.99). Three of these 4 patients also displayed minimal interaction with voriconazole (AUC ratios 1.08-1.96); baseline ibrutinib AUCs for the 3 patients were at the high end of the range, indicating lower CYP3A abundance and thus less impact from CYP inhibition.

Physiologically-based PK modeling under fed conditions predicted a 5.5- and 7.1-fold increase in the GMR for ibrutinib C_max and AUC, respectively, when dosed with erythromycin and an increase of 6.3- and 7.6-fold, respectively, when dosed with voriconazole. The simulated interaction factor for voriconazole is contained in the 90% CI of the observed GMRs (borderline for AUC), whereas the model over-predicted C_max and AUC by ~50% and ~130%, respectively.

Treatment-emergent adverse events (TEAEs) were reported in 22/26 patients (85%); The most common TEAEs (all causality, ≥ 10% of patients) were diarrhea (27%); neutropenia (23%); abdominal pain, fatigue, pyrexia, and thrombocytopenia (15% each); anemia, dry mouth, cough, dyspnea, and hypertension (12% each). Drug-related TEAEs ≥ grade 3 were neutropenia (15.4%); hypertension (7.7%); and diarrhea, thrombocytopenia, herpes zoster, cough, dyspnea, atrial fibrillation, and cardiac failure (3.8% each).

Conclusions:PK data indicate that 140 mg ibrutinib, when combined with a moderate or strong CYP3A inhibitor, achieved exposures generally consistent with those after a 560 mg dose given alone. Coadministration of 140 mg ibrutinib with erythromycin or voriconazole demonstrated an acceptable safety profile, and the adverse event profile was consistent with the ibrutinib safety profile at therapeutic doses. These findings support the 140 mg/day ibrutinib dose when given in combination with erythromycin or voriconazole.

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