Posaconazole‐ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment

Abstract

AimsIbrutinib is used in the treatment of certain B‐cell malignancies. Due to its CYP3A4‐mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug‐drug interactions.MethodsIn a randomized, placebo‐controlled, three‐phase crossover study, we examined the effect of the CYP3A4‐inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose.ResultsOn average, morning posaconazole increased the dose‐adjusted geometric mean area under the plasma concentration‐time curve from zero to infinity (AUC0‐∞) and peak plasma concentration (Cmax) of ibrutinib 9.5‐fold (90% confidence interval [CI] 6.3‐14.3, P < 0.001) and 8.5‐fold (90% CI 5.7‐12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3‐fold (90% CI 6.7‐16.0, P < 0.001) and 8.2‐fold (90% CI 5.2‐13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half‐life of ibrutinib, but substantially reduced the metabolite PCI‐45227 to ibrutinib AUC0‐∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases.ConclusionsPosaconazole increases ibrutinib exposure substantially, by about 10‐fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70‐mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.