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Assessment of Potential Drug-Drug Interactions for Novel Oral Melanocortin-1 Receptor Agonist Dersimelagon.
- Source :
-
Pharmacology research & perspectives [Pharmacol Res Perspect] 2025 Feb; Vol. 13 (1), pp. e70069. - Publication Year :
- 2025
-
Abstract
- Dersimelagon is a novel investigational orally administered selective agonist of the melanocortin-1 receptor. The drug-drug interaction (DDI) potential of dersimelagon was investigated in both nonclinical (in vitro) and clinical studies. The in vitro inhibition of CYP/UGT isoforms and efflux/uptake transporters by dersimelagon was assessed. The impact of 300-mg dersimelagon on the pharmacokinetics (PK) of substrate drugs and the effect of co-administering verapamil on 100-mg dersimelagon PK (as substrate drug) were investigated in healthy participants in a Phase 1 study. DDIs were assessed based on ratios of C <subscript>max</subscript> and AUC <subscript>0-∞</subscript> of substrate drug administered alone and with dersimelagon (or verapamil). Relatively potent in vitro inhibition of CYP2C9, CYP3A, UGT1A1, BCRP, P-gp, and OATPs by dersimelagon was observed. In the clinical study, exposures of atorvastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabolite of simvastatin) increased 2- to 3-fold (atorvastatin: C <subscript>max</subscript> LS mean ratio = 198.0%; AUC <subscript>0-∞</subscript> ratio = 196.6%; rosuvastatin: C <subscript>max</subscript> ratio = 316.5%, AUC <subscript>0-∞</subscript> ratio = 206.0%) when co-administered with dersimelagon. Midazolam (CYP3A substrate), digoxin (P-gp), pravastatin (OATP), and simvastatin (CYP3A) did not show any clinically relevant DDI effects when co-administered with dersimelagon. Dersimelagon exposure increased ~25% when co-administered with verapamil, an effect not considered clinically relevant. Dersimelagon 300 mg did not elicit major DDIs involving CYP/UGT enzymes and drug transporters; however, dersimelagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvastatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs. Trial Registration: ClinicalTrials.gov: NCT04793295, NCT04402489, NCT04440592, NCT02834442, NCT03520036, NCT03503266.<br /> (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
- Subjects :
- Humans
Male
Adult
Young Adult
Female
Administration, Oral
Middle Aged
Verapamil pharmacology
Verapamil pharmacokinetics
Verapamil administration & dosage
Rosuvastatin Calcium pharmacokinetics
Rosuvastatin Calcium administration & dosage
Atorvastatin pharmacokinetics
Atorvastatin administration & dosage
Atorvastatin pharmacology
Animals
Cross-Over Studies
Glucuronosyltransferase metabolism
Midazolam pharmacokinetics
Midazolam administration & dosage
Area Under Curve
Healthy Volunteers
Digoxin pharmacokinetics
Digoxin administration & dosage
Cytochrome P-450 Enzyme System metabolism
Drug Interactions
Subjects
Details
- Language :
- English
- ISSN :
- 2052-1707
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Pharmacology research & perspectives
- Publication Type :
- Academic Journal
- Accession number :
- 39887900
- Full Text :
- https://doi.org/10.1002/prp2.70069