Dersimelagon

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 Cmax and AUC0‐∞ 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: Cmax LS mean ratio = 198.0%; AUC0‐∞ ratio = 196.6%; rosuvastatin: Cmax ratio = 316.5%, AUC0‐∞ 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