Journal article
Cyclodextrin-Based Inclusion Complexes Improve the In Vitro Solubility and Pharmacokinetics of Ivacaftor Following Oral Administration in Mice
AAPS PharmSciTech, Vol.26(5), 135
05/16/2025
DOI: 10.1208/s12249-025-03131-6
PMCID: PMC12765454
PMID: 40379997
Appears in UI Libraries Support Open Access
Abstract
Cystic fibrosis is a serious life-threatening hereditary disease that occurs due to a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Ivacaftor (IVA) is a drug that targets the mutated CFTR protein. IVA is highly hydrophobic (log P = 5.6) with poor aqueous solubility (0.05 µg/mL) and is formulated as an amorphous solid dispersion tablet under the brand name Kalydeco®. The recommended daily dose of Kalydeco® is twice per day with a high fat meal to aid in IVA's absorption. In this research, we studied the application of cyclodextrins (CDs) to improve the dissolution of IVA. Phase solubility studies between IVA and four different CDs (α-, β-, γ-, and hydroxypropyl-β-CD [HP-β-CD]) were conducted and a significant improvement in IVA's aqueous solubility with HP-β-CD was observed. Solid state characterizations confirmed the formation of IVA/HP-β-CD inclusion complexes. In vitro dissolution studies were conducted at pH = 6.8 and showed improvement in IVA's rate and extent of dissolution with IVA/HP-β-CD (1:2) complexes in comparison to uncomplexed IVA. In vivo pharmacokinetics in mice showed a 2-fold increase in area under the curve (AUC) after the oral administration of the IVA/HP-β-CD complex in comparison to Kalydeco tablets. In addition, HP-β-CD extended the release of IVA from the IVA/HP-β-CD complexes with a longer Tmax of 7.05 h compared to 2.96 h with Kalydeco® tablets. These results demonstrate that CD inclusion complexes of IVA using HP-β-CD can be a successful alternative approach to improving the solubility of IVA while extending its release.
Details
- Title: Subtitle
- Cyclodextrin-Based Inclusion Complexes Improve the In Vitro Solubility and Pharmacokinetics of Ivacaftor Following Oral Administration in Mice
- Creators
- David S. Nakhla - University of IowaYoussef W. Naguib - University of Iowa, Pharmaceutical Sciences and Experimental TherapeuticsSanjib Saha - University of IowaDylan Gao - University of IowaNikesh Gupta - University of IowaWalla Malkawi - University of IowaTimothy M. Acri - University of IowaAliasger K. Salem - University of Iowa
- Resource Type
- Journal article
- Publication Details
- AAPS PharmSciTech, Vol.26(5), 135
- DOI
- 10.1208/s12249-025-03131-6
- PMID
- 40379997
- PMCID
- PMC12765454
- NLM abbreviation
- AAPS PharmSciTech
- ISSN
- 1530-9932
- eISSN
- 1530-9932
- Publisher
- Springer Nature; NEW YORK
- Grant note
- National Institute of Health: P30 CA086862 Lyle and Sharon Bighley Chair in Pharmaceutical Sciences grant
This work was supported in part by the National Institute of Health grant (P30 CA086862) and the Lyle and Sharon Bighley Chair in Pharmaceutical Sciences grant.
- Language
- English
- Date published
- 05/16/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Research Administration; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9984823067402771
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