Acalabrutinib CYP3A mediated Drug-Drug Interactions: Clinical Evaluations and Physiologically-Based Pharmacokinetic Modeling to inform dose adjustment strategy

Aims: Clinical drug interaction studies with itraconazole and rifampicin demonstrated acalabrutinib is a sensitive substrate of CYP3A. A PBPK model was developed based on the data of these studies. One of the active CYP3A metabolite ACP-5862 was identified but never studied in a drug interaction scenario. This study aims to evaluate both parent and metabolite exposure change with coadministration of moderate CYP3A inhibitors and its impact on safety and efficacy.

Method: In an open label, randomized, 2-period study, we investigated the effect of coadministration of fluconazole or isavuconazole on the pharmacokinetics of acalabrutinib. BTK receptor occupancy and safety was compared between different treatments. Experimental data was compared to PBPK simulation results.

Result: Least square means of Acalabrutinib Cmax and AUC increased 1.37(1.14-1.64)and 1.60(1.45-1.77)-fold in the presence of isavuconazole and 1.48(1.10-1.98) and 2.16(1.94-2.40) fold in the presence of fluconazole, respectively. For ACP-5862, these values are 0.72(0.63-0.82) and 0.91(0.86-0.97) fold for isavuconazole and 0.65(0.49-0.87) and 0.95(0.91-0.99) fold for fluconazole coadministration. The PBPK model was able to recover acalabrutinib and ACP-5862 PK profiles in the study. BTK receptor occupancy change was minimal in the presence of isavuconazole. There were no deaths, SAEs, or subject discontinuation due to AEs in this study. Mild (Grade 1) AEs were the only AEs reported during the study, by 17% of the study population.

Conclusion: Our results demonstrated the impact of fluconazole and isavuconazole on the pharmacokinetics of acalabrutinib and ACP-5862 and suggests no dose adjustment is needed for concomitant administration with moderate CYP3A inhibitors. Current PBPK model can be used to propose dose adjustment for drug interactions via CYP3A.

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