Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6

Abstract

Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (C_max ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the C_max and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.

Trial registration: ClinicalTrials.gov NCT03301207.

Keywords: Cytochrome P450; drug interactions; pharmacokinetics; phase I.

Figure 1

Mean plasma concentration‐time curves: (A) ethinylestradiol; (B) levonorgestrel; (C) midazolam; (D) 1‐OH‐midazolam; (E) bupropion; (F) 4‐OH‐bupropion. ^aAUC_last is presented because AUC_∞ was not calculable for > 50% of samples. AUC_∞, area under the plasma concentration‐time curve from 0 to infinite time; AUC_last, area under the plasma concentration‐time curve from 0 to last measurable concentration; EE, ethinylestradiol; LN, levonorgestrel; OCs, oral contraceptives; QD, once daily

Figure 2

AUC scatterplots of study drugs and their metabolites alone and in the presence of ibrutinib: (A) ethinylestradiol; (B) levonorgestrel; (C) midazolam; (D) 1‐OH‐midazolam; (E) bupropion; (F) 4‐OH‐bupropion. Open circles represent mean values. AUC_last for levonorgestrel and 4‐OH‐bupropion is presented because AUC_∞ was not calculable for > 50% of profiles. AUC_∞, area under the plasma concentration‐time curve from 0 to infinite time; AUC_last, area under the plasma concentration‐time curve from 0 to last measurable concentration