Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs
Calquence<sup>®</sup> (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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/4/557 |
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| author | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Nishant Biswas Molly S. Adam Adam Smith Christopher D. Craig Michael M. Morgen David T. Vodak |
| author_facet | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Nishant Biswas Molly S. Adam Adam Smith Christopher D. Craig Michael M. Morgen David T. Vodak |
| author_sort | Deanna M. Mudie |
| collection | DOAJ |
| description | Calquence<sup>®</sup> (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. |
| first_indexed | 2024-03-10T12:17:27Z |
| format | Article |
| id | doaj.art-881f3a4a898c49bfb5e5f8d977530edb |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T12:17:27Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-881f3a4a898c49bfb5e5f8d977530edb2023-11-21T15:45:09ZengMDPI AGPharmaceutics1999-49232021-04-0113455710.3390/pharmaceutics13040557Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in DogsDeanna M. Mudie0Aaron M. Stewart1Jesus A. Rosales2Nishant Biswas3Molly S. Adam4Adam Smith5Christopher D. Craig6Michael M. Morgen7David T. Vodak8Global Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USAGlobal Research & Development, Lonza, Bend, OR 97703, USACalquence<sup>®</sup> (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.https://www.mdpi.com/1999-4923/13/4/557acalabrutinibamorphous solid dispersionacid-reducing agentbioavailability enhancementkinase inhibitorpH effect |
| spellingShingle | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Nishant Biswas Molly S. Adam Adam Smith Christopher D. Craig Michael M. Morgen David T. Vodak Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs Pharmaceutics acalabrutinib amorphous solid dispersion acid-reducing agent bioavailability enhancement kinase inhibitor pH effect |
| title | Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs |
| title_full | Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs |
| title_fullStr | Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs |
| title_full_unstemmed | Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs |
| title_short | Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs |
| title_sort | amorphous solid dispersion tablets overcome acalabrutinib ph effect in dogs |
| topic | acalabrutinib amorphous solid dispersion acid-reducing agent bioavailability enhancement kinase inhibitor pH effect |
| url | https://www.mdpi.com/1999-4923/13/4/557 |
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