Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay.
| Title: | Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay. |
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| Authors: | Bi, Yi‐An, Jordan, Samantha, King‐Ahmad, Amanda, West, Mark A., Varma, Manthena V. S. |
| Source: | Clinical Pharmacology & Therapeutics; Jun2024, Vol. 115 Issue 6, p1336-1345, 10p |
| Subject Terms: | CHRONIC kidney failure, DRUG interactions, RIFAMPIN, PHARMACOKINETICS, KRA, HYPOXIA-inducible factors, ERYTHROPOIETIN receptors |
| Abstract: | Daprodustat is the first oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B‐mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically‐based PK (PBPK) modeling of its drug–drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single‐dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2‐fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady‐state was also reduced by 5.0 ± 1.1‐fold, whereas the half‐life change was minimal (1.5‐fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B‐CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18‐fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well‐captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate‐to‐strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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| Items | – Name: Title Label: Title Group: Ti Data: Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Bi%2C+Yi‐An%22">Bi, Yi‐An</searchLink><br /><searchLink fieldCode="AR" term="%22Jordan%2C+Samantha%22">Jordan, Samantha</searchLink><br /><searchLink fieldCode="AR" term="%22King‐Ahmad%2C+Amanda%22">King‐Ahmad, Amanda</searchLink><br /><searchLink fieldCode="AR" term="%22West%2C+Mark+A%2E%22">West, Mark A.</searchLink><br /><searchLink fieldCode="AR" term="%22Varma%2C+Manthena+V%2E+S%2E%22">Varma, Manthena V. S.</searchLink> – Name: TitleSource Label: Source Group: Src Data: Clinical Pharmacology & Therapeutics; Jun2024, Vol. 115 Issue 6, p1336-1345, 10p – Name: Subject Label: Subject Terms Group: Su Data: <searchLink fieldCode="DE" term="%22CHRONIC+kidney+failure%22">CHRONIC kidney failure</searchLink><br /><searchLink fieldCode="DE" term="%22DRUG+interactions%22">DRUG interactions</searchLink><br /><searchLink fieldCode="DE" term="%22RIFAMPIN%22">RIFAMPIN</searchLink><br /><searchLink fieldCode="DE" term="%22PHARMACOKINETICS%22">PHARMACOKINETICS</searchLink><br /><searchLink fieldCode="DE" term="%22KRA%22">KRA</searchLink><br /><searchLink fieldCode="DE" term="%22HYPOXIA-inducible+factors%22">HYPOXIA-inducible factors</searchLink><br /><searchLink fieldCode="DE" term="%22ERYTHROPOIETIN+receptors%22">ERYTHROPOIETIN receptors</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Daprodustat is the first oral hypoxia‐inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B‐mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically‐based PK (PBPK) modeling of its drug–drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single‐dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2‐fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady‐state was also reduced by 5.0 ± 1.1‐fold, whereas the half‐life change was minimal (1.5‐fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B‐CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18‐fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well‐captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate‐to‐strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation. [ABSTRACT FROM AUTHOR] – Name: Abstract Label: Group: Ab Data: <i>Copyright of Clinical Pharmacology & Therapeutics is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1002/cpt.3215 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 10 StartPage: 1336 Subjects: – SubjectFull: CHRONIC kidney failure Type: general – SubjectFull: DRUG interactions Type: general – SubjectFull: RIFAMPIN Type: general – SubjectFull: PHARMACOKINETICS Type: general – SubjectFull: KRA Type: general – SubjectFull: HYPOXIA-inducible factors Type: general – SubjectFull: ERYTHROPOIETIN receptors Type: general Titles: – TitleFull: Mechanistic Determinants of Daprodustat Drug–Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B‐CYP2C8 Interplay. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Bi, Yi‐An – PersonEntity: Name: NameFull: Jordan, Samantha – PersonEntity: Name: NameFull: King‐Ahmad, Amanda – PersonEntity: Name: NameFull: West, Mark A. – PersonEntity: Name: NameFull: Varma, Manthena V. S. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 06 Text: Jun2024 Type: published Y: 2024 Identifiers: – Type: issn-print Value: 00099236 Numbering: – Type: volume Value: 115 – Type: issue Value: 6 Titles: – TitleFull: Clinical Pharmacology & Therapeutics Type: main |
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