In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets
Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosag...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/8/1257 |
| _version_ | 1797522336326352896 |
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| author | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Molly S. Adam Michael M. Morgen David T. Vodak |
| author_facet | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Molly S. Adam Michael M. Morgen David T. Vodak |
| author_sort | Deanna M. Mudie |
| collection | DOAJ |
| description | Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC<sub>0-inf</sub> < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products. |
| first_indexed | 2024-03-10T08:27:59Z |
| format | Article |
| id | doaj.art-184cec856c934b98b8bbbecf586d8fd1 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T08:27:59Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-184cec856c934b98b8bbbecf586d8fd12023-11-22T09:15:04ZengMDPI AGPharmaceutics1999-49232021-08-01138125710.3390/pharmaceutics13081257In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion TabletsDeanna M. Mudie0Aaron M. Stewart1Jesus A. Rosales2Molly S. Adam3Michael M. Morgen4David T. Vodak5Global 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, USAAmorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC<sub>0-inf</sub> < 2). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.https://www.mdpi.com/1999-4923/13/8/1257acalabrutinibamorphous solid dispersionbioavailability enhancementacid reducing agentproton pump inhibitorkinase inhibitor |
| spellingShingle | Deanna M. Mudie Aaron M. Stewart Jesus A. Rosales Molly S. Adam Michael M. Morgen David T. Vodak In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets Pharmaceutics acalabrutinib amorphous solid dispersion bioavailability enhancement acid reducing agent proton pump inhibitor kinase inhibitor |
| title | In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets |
| title_full | In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets |
| title_fullStr | In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets |
| title_full_unstemmed | In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets |
| title_short | In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets |
| title_sort | in vitro in silico tools for streamlined development of acalabrutinib amorphous solid dispersion tablets |
| topic | acalabrutinib amorphous solid dispersion bioavailability enhancement acid reducing agent proton pump inhibitor kinase inhibitor |
| url | https://www.mdpi.com/1999-4923/13/8/1257 |
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