1. Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform.
- Author
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Lennernäs H, Brisander M, Liljebris C, Jesson G, and Andersson P
- Subjects
- Humans, Male, Administration, Oral, Nanoparticles, Solubility, Adult, Therapeutic Equivalency, Drug Compounding, Tablets, Young Adult, Cross-Over Studies, Female, Dasatinib pharmacokinetics, Dasatinib administration & dosage, Sorafenib pharmacokinetics, Sorafenib administration & dosage, Biological Availability, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors blood
- Abstract
Despite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle-amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate-release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib-ASD, 100 mg tablet) and XS005 (sorafenib-ASD, 2 × 50 mg capsules) were compared with their crystalline formulated reference drugs (140 mg of dasatinib-reference and 200 mg of sorafenib-reference). The in vitro biopharmaceutics of dasatinib-ASD and XS005-granulate showed sustained increased solubility in the pH range 1.2-8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1-4.8 times lower intra- and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2-2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH-dependent absorption process., (© 2024 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2024
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