Bioequivalence and Relative Bioavailability Studies to Assess a New Acalabrutinib Formulation That Enables Coadministration With Proton-Pump Inhibitors

Publication: Clin Pharmacol Drug Dev
Division: PBPK


Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia,small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinibcapsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration withproton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N=30, N=66, N=20)evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet(AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fedstate, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometricmean [% coefficient of variation,CV]) were comparable for AT versus AC (AUCinf567.8 ng h/mL [36.9] vs 572.2 ng h/mL[38.2],Cmax537.2 ng/mL [42.6] vs 535.7 ng/mL [58.4],respectively);similar results were observed for acalabrutinib’s activemetabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean Cmaxfor acalabrutinib was lower when ATwas administered in the fed versus the fasted state (Cmax255.6 ng/mL [%CV, 46.5] vs 504.9 ng/mL [49.9]); AUCs weresimilar. For AT+PPI, geometric mean Cmaxwas lower (371.9 ng/mL [%CV, 81.4] vs 504.9 ng/mL [49.9]) and AUCinfwashigher (AUCinf694.1 ng h/mL [39.7] vs 559.5 ng h/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy.Most adverse events were mild with no new safety concerns.Acalabrutinib formulations were comparable and AT couldbe coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.

By Shringi Sharma, Xavier Pepin, Harini Burri, Lianqing Zheng,Nataliya Kuptsova-Clarkson, Anouk de Jong, Ting Yu, Holly L. MacArthur,Michal Majewski, John C. Byrd, Richard R. Furman,Joseph A.Ware, James Mann,David Ramies, Veerendra Munugalavadla, Louise Sheridan, and Helen Tomkinson