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 dersim- elagon 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 ator- vastatin (CYP3A, P-gp, BCRP, OATP substrate) rosuvastatin (BCRP and OATP substrate), and β-hydroxy simvastatin (metabo- lite 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 der- simelagon. 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, dersim- elagon may have potential for clinically relevant DDIs with drugs that are substrates for BCRP, such as atorvastatin and rosuvas- tatin, and caution should be exercised when co-administering 300-mg dersimelagon with these statin drugs.