Abstract
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.
Highlights
Calquence® is a commercially marketed kinase inhibitor used as second-line therapy for adult patients seeking treatment for mantle cell lymphoma, chronic lymphocytic leukemia, or small lymphocytic lymphoma [1]
A 50/50 (% w/w) acalabrutinib/HPMCAS-H amorphous solid dispersion (ASD) was spray dried with a high yield
Powder X-ray diffraction (PXRD) showed no evidence of crystallinity, based on the absence of sharp diffraction peaks characteristic of crystalline acalabrutinib
Summary
Calquence® is a commercially marketed kinase inhibitor used as second-line therapy for adult patients seeking treatment for mantle cell lymphoma, chronic lymphocytic leukemia, or small lymphocytic lymphoma [1]. In Calquence is the crystalline Form I of acalabrutinib, which is a diprotic weak base with pKa values of 3.5 and 5.8 [2]. It is a Biopharmaceutics Classification System (BCS) Class 2 drug with low intrinsic solubility and a moderate log P [2,3]. Calquence has clinically meaningful drug–drug interactions (DDIs) with acid-reducing agents (ARAs) such as proton pump inhibitors (PPIs), where concomitant use results in reduced area under the plasma drug concentration–time curve (AUC) values [4]. Coadministration of Calquence with 40 mg of the PPI omeprazole for 5 days decreased
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