Pharmacokinetics of Asciminib When Taken With Imatinib or With Food

Abstract

Asciminib, a first‐in‐class, Specifically Targeting the Abelson kinase Myristoyl Pocket (STAMP) inhibitor with the potential to overcome resistance to adenosine triphosphate–competitive tyrosine kinase inhibitors, is being investigated in leukemia as monotherapy and in combination with tyrosine kinase inhibitors including imatinib. This phase 1 study in healthy volunteers assessed the pharmacokinetics of asciminib (40 mg single dose) under 2 conditions: when taken with imatinib (steady state; 400 mg once daily) and a low‐fat meal (according to imatinib prescription information), or when taken as single‐agent under different food conditions. Asciminib plus imatinib with a low‐fat meal increased asciminib area under the plasma concentration–time curve from time 0 to infinity and maximum plasma concentration (geometric mean ratios [90% confidence interval], 2.08 [1.93‐2.24] and 1.59 [1.45‐1.75], respectively) compared with asciminib alone under the same food conditions. Asciminib plus food decreased asciminib area under the plasma concentration–time curve from time 0 to infinity compared with asciminib taken under fasted conditions (geometric mean ratios: low‐fat meal, 0.7 [0.631‐0.776]; high‐fat meal, 0.377 [0.341‐0.417]). Asciminib plus imatinib was well tolerated with no new safety signals. Overall, coadministration of asciminib with imatinib and a low‐fat meal results in a moderate increase in asciminib exposure compared with asciminib alone under the same food condition. Food itself decreases asciminib exposure, indicating that single‐agent asciminib should be administered in the fasted state to prevent potential suboptimal exposures.

Relative Bioavailability and Food Effect of Asciminib Pediatric Mini‐tablet Formulation Compared to the Reference Tablet Formulation in Healthy Adult Participants

“…Using an assumed intraparticipant CV of 29% (based on the largest GCV% of AUC inf , AUC last , and C max from previous asciminib PK studies 11,15 ) and a sample size of 18, the precision or half-width of the 90%CI for test-reference comparison on the log scale was extended 0.1648 from the observed difference in means. This calculation was based on a paired t-test with two-sided alpha level of 10% and 17°of freedom.…”

“…Plasma concentrations of asciminib were measured as previously described using a validated liquid chromatographytandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 1.0 ng/mL. 11 To assess the acceptability and palatability, participants completed a questionnaire in which they were asked to rate (very good, good, neither good nor bad, bad, or very bad) the treatments based on the ease of ingesting the tablets, after-taste, smell, and feel in the mouth of the asciminib reference tablet and mini-tablets. The questionnaire was completed within 15 minutes of each drug administration.…”

“…10 A food effect analysis showed that administration of asciminib with food reduced exposure, the effect of which was more pronounced with higher dietary fat content. 11 Similarly, administration of asciminib with food compared with fasted conditions delayed t max and the change in t max increased with dietary fat content. 11 Asciminib was evaluated in the pivotal phase III randomized controlled trial, ASCEMBL (NCT03106779), in which asciminib 40 mg twice daily (BID) demonstrated superior efficacy and improved safety and tolerability versus bosutinib 500 mg once daily in adult patients with CML-CP who had been treated with ≥2 prior adenosine triphosphate (ATP)-competitive TKIs.…”

“…11 Similarly, administration of asciminib with food compared with fasted conditions delayed t max and the change in t max increased with dietary fat content. 11 Asciminib was evaluated in the pivotal phase III randomized controlled trial, ASCEMBL (NCT03106779), in which asciminib 40 mg twice daily (BID) demonstrated superior efficacy and improved safety and tolerability versus bosutinib 500 mg once daily in adult patients with CML-CP who had been treated with ≥2 prior adenosine triphosphate (ATP)-competitive TKIs. 12 For adult patients, asciminib 20-and 40mg film-coated tablets have been developed.…”

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

“…Asciminib (ABL001) is an oral BCR::ABL1 inhibitor with a mechanism of action distinct from currently approved ATP‐competitive tyrosine kinase inhibitors (TKIs) used for the treatment of chronic myeloid leukemia (CML). Asciminib is the first‐in‐class BCR::ABL1 inhibitor specifically targeting the BCR::ABL1 myristoyl pocket (STAMP inhibitor) 1–4 . The unique mechanism of action of asciminib means that this drug can maintain activity against forms of BCR::ABL1 carrying resistance mutations (including the T315I mutation) in the ATP‐binding site, thereby becoming a novel treatment option for patients who no longer respond to currently available TKIs 1–3 …”