Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition

Abstract

Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform–mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms (CYP3A−/−) that received ibrutinib alone or in combination with CYP3A inhibitors cobicistat or ketoconazole. Computational modeling was performed to derive doses of ibrutinib that, when given after a CYP3A inhibitor, results in therapeutically relevant drug levels. Deficiency of CYP3A in mice was associated with an approximately 10-fold increase in the AUC of ibrutinib. This result could be phenocopied by administration of cobicistat before ibrutinib in wild-type mice, but cobicistat did not influence levels of ibrutinib in CYP3A−/− mice. Population pharmacokinetic and prospectively validated physiologically based pharmacokinetic models established preclinical and clinical doses of ibrutinib that could be given safely in combination with cobicistat without negatively affecting antileukemic properties. These findings signify a dominant role for CYP3A-mediated metabolism in the elimination of ibrutinib, and suggest a role for pharmacologic inhibitors of this pathway to intentionally modulate the plasma levels and improve the therapeutic use of this clinically important agent. Significance: Ibrutinib has limited oral bioavailability, which contributes to significant interindividual pharmacokinetic variability. Using engineered mouse models, we here report a causal relationship between CYP3A-mediated metabolism and ibrutinib's bioavailability and drug–drug interaction with cobicistat. These results offer a mechanistic basis for reported pharmacokinetic interactions with ibrutinib, and in conjunction with a newly developed computational model, allow for the rational design of clinical trials aimed at improving the therapeutic use of ibrutinib.

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

“…However, using the 140‐mg dose of ibrutinib with posaconazole, as recommended in the European prescribing information, will lead to exposures that markedly exceed those with standard daily doses in most individuals, likely leading to risk of concentration‐dependent adverse effects. Similar to the above suggestions, both the average change in bioavailability or AUC and reduction in interindividual variability should be taken into account if CYP3A inhibitor drug‐drug interactions are intentionally used to boost ibrutinib pharmacokinetics, as suggested previously 11,32–34 …”

“…Similar to the above suggestions, both the average change in bioavailability or AUC and reduction in interindividual variability should be taken into account if CYP3A inhibitor drug-drug interactions are intentionally used to boost ibrutinib pharmacokinetics, as suggested previously. 11,[32][33][34] It has been suggested that CYP3A4 inhibitors can be intentionally used together with ibrutinib to reduce its cost. 11,34,35 The financial burden of standard-dose ibrutinib treatment is extensive.…”

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

“…Since dofetilide is at least partially metabolized by CYP3A4, it has been suggested that concurrent administration of dofetilide with inhibitors of this enzyme could potentially result in an increase in the plasma concentrations of Dofetilide [ 24 , 49 , 50 ]. To explore the likelihood of this interaction mechanism, we next performed pharmacokinetic studies with dofetilide in mice lacking all CYP3A isoforms (CYP3A −/− mice) [ 51 ]. These studies revealed that the deficiency of CYP3A did not significantly influence the concentrations of dofetilide in plasma ( Figure 5 A,B,D,G) or urine ( Figure 5 C) after oral or i.v.…”

Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice

“…Microsomal Experiments. The liver metabolism of vincristine was conducted in vitro using mouse and human liver microsomes as previously described (Eisenmann et al, 2021). All assays were conducted in a total volume of 100 μL.…”