Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required.

In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance.

In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

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Article information: Mudie, D.M.M.; Stewart, A.M.M.; Rosales, J.A.A.; Biswas, N.; Adam, M.S.S.; Smith, A.; Craig, C.D.D.; Morgen, M.M.M.; Vodak, D.T.T. Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs. Pharmaceutics 2021, 13, 557. https://doi.org/10.3390/pharmaceutics13040557

Materials: Acalabrutinib (CAS 1420477-60-6, >98% purity) was purchased from LC Laboratories (Woburn, MA, USA). HPMCAS-HF (Aqoat, HF grade) was purchased from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Hydrochloric acid (HCl), sodium acetate, sodium phosphate, potassium phosphate, and sodium chloride (NaCl) were purchased from Sigma Aldrich Chemical Company (St. Louis, MO, USA). Ammonium acetate was purchased from Thermo Fisher Scientific (Waltham, MA, USA). Fasted-state simulated intestinal fluid (FaSSIF) powder was purchased from Biorelevant.com Ltd. (London, UK). Methanol (HPLC grade) was purchased from Honeywell (Morris Plains, NJ, USA). Calquence capsules were purchased from Drug World (Cold Spring, NY, USA). Avicel PH-101 (microcrystalline cellulose) was purchased from FMC Corporation (Philadelphia, PA, USA). Pearlitol 25 (mannitol) was purchased from Roquette America (Geneva, IL, USA). Ac-Di-Sol (croscarmellose sodium) was purchased from Dupont (Wilmington, DE, USA). Cab-O-Sil M5P (fumed silica) was purchased from Cabot Corporation (Alpharetta, GA, USA). Magnesium stearate was purchased from Macron Fine Chemicals/Avantor (Radnor, PA, USA). Covance Laboratories (Madison, WI, USA) purchased pentagastrin from Sigma Aldrich Chemical Company and famotidine from Kirkland Signature (Kirkland, WA, USA) for use in in vivo testing.