Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents

Publication: Clin Transl Sci
Software: GastroPlus®


Asciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40-fold excess to itraconazole] in the oral solution formulationof itraconazole)decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by~13–15%) and the strong P-gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P-gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin-containing drug formulations.

By Matthias Hoch, Felix Huth, Masahiko Sato, Tirtha Sengupta, Michelle Quinlan, Stephanie Dodd, Shruti Kapoor, Florence Hourcade-Potelleret