Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction

Abstract

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC0-∞ ) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P < 0.001) and peak plasma concentration (Cmax ) 8.8-fold (90% CI 6.3-12.1; P < 0.001). During itraconazole, the intersubject variation for the AUC0-∞ (55%) and Cmax (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

The plasma concentrations of ibrutinib in a randomized crossover study in 11 healthy subjects after a single 140‐mg (placebo phase) or 15‐mg (itraconazole phase) oral dose of ibrutinib on day 3 of a 4‐day pretreatment with 200 mg itraconazole or placebo twice daily on day 1 and once daily on days 2–4. Data are given for both the ibrutinib concentrations adjusted to a 140‐mg dose (a) and the unadjusted concentrations (b) and are presented as geometric means with 90% confidence intervals. For clarity, some error bars have been omitted. Insets depict the same data on a semilogarithmic scale.

Figure 2

The unadjusted individual plasma concentration‐time curves of ibrutinib in placebo (a) and itraconazole (b) phases, as well as the unadjusted individual area under the plasma concentration time curves from zero to infinity (AUC0–∞) (c) and peak plasma concentrations (Cmax) (d) of ibrutinib in placebo and itraconazole phases with 90% confidence intervals. Eleven healthy subjects received in a randomized crossover study either a single 140‐mg (placebo phase) or 15‐mg (itraconazole phase) oral dose of ibrutinib on day 3 of a 4‐day pretreatment with 200 mg itraconazole or placebo twice daily on day 1 and once daily on days 2–4. The bold lines in figures (a) and (b) represent the geometric means.

Figure 3

The correlation of the PCI‐45227:ibrutinib area under the plasma concentration time curve from zero to infinity (AUC0–∞) ratio in the placebo phase with the ibrutinib AUC0–∞ itraconazole to control ratio (a), and the correlation of itraconazole AUC0–5 hours with the ibrutinib AUC0–∞ itraconazole to control ratio (b).

Figure 4

The plasma concentrations of ibrutinib's metabolite PCI‐45227 in a randomized crossover study in 11 healthy subjects after a single 140‐mg (placebo phase) or 15‐mg (itraconazole phase) oral dose of ibrutinib on day 3 of a 4‐day pretreatment with 200 mg itraconazole or placebo twice daily on day 1 and once daily on days 2–4. Data are given for both the ibrutinib concentrations adjusted to a 140‐mg dose (a) as well as the unadjusted concentrations (b) and is presented as geometric means with 90% confidence intervals. For clarity, some error bars have been omitted. Insets depict the same data on a semilogarithmic scale.