title: Pharmacokinetic interactions between alitretinoin and ketoconazole or simvastatin or ciclosporin A.
abstract: BACKGROUND
  Based on in vitro data with isolated cytochrome P450 (CYP) isoenzymes, alitretinoin interacts only with CYP3A4, and the potential for drug-drug interactions is considered negligible.
  
  
  OBJECTIVE
  To confirm in humans the lack of potential interactions between CYP3A4 and alitretinoin in vivo.
  
  
  METHODS
  This was a multiple-dose, open-label, parallel-group, single-centre study, which enrolled 54 healthy male volunteers aged 18-45 years. Subjects were divided into three groups, with 18 in each group: group 1 received either alitretinoin 30 mg and ketoconazole 200 mg, group 2 alitretinoin 30 mg and simvastatin 40 mg, and group 3 alitretinoin 30 mg and ciclosporin A 300-mg.
  
  
  RESULTS
  At the highest therapeutic dose of 30 mg, alitretinoin had no significant effect on the pharmacokinetics (PK) of ketoconazole and ciclosporin A. There was a significant but not clinically relevant effect of simvastatin on the area under the curve (AUC) of plasma concentration vs. time and on maximum plasma concentration (C(max)) after repeated administration of alitretinoin. Exposure to simvastatin concomitantly with alitretinoin was decreased by 16% for AUC and 23% for C(max). The CYP3A4 ± PgP substrates of simvastatin and ciclosporin A did not affect the single or repeated dose PK of alitretinoin. The strong CYP3A4/PgP inhibitor ketoconazole led to significant increases in both AUC and C(max) values for alitretinoin.
  
  
  CONCLUSIONS
  Single and repeated doses of alitretinoin do not alter the PK of ciclosporin A and ketoconazole. Simvastatin levels were slightly but significantly reduced by co-administration of alitretinoin. Substrates of CYP3A4 did not affect the PK of alitretinoin. However, ketoconazole significantly increased the plasma levels of alitretinoin, therefore, co-administration with CYP3A4 inhibitors such as ketoconazole may require a dose reduction of alitretinoin.
authors: Basilea Pharmaceutica International Ltd, Basel, Switzerland. anne.schmitt-hoffmann@basilea.com
authors: A H
authors: AH
authors: Schmitt-Hoffmann
authors: B
authors: B
authors: Roos
authors: J
authors: J
authors: Sauer
authors: J
authors: J
authors: Spickermann
authors: J
authors: J
authors: Maares
authors: A
authors: A
authors: Schoetzau
authors: I
authors: I
authors: Meyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000077556:Alitretinoin; D000935:Antifungal Agents / Q000097:blood; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000097:blood*; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood; D007166:Immunosuppressive Agents / Q000097:blood; D007654:Ketoconazole / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000097:blood*; D014212:Tretinoin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D003879:Dermatologic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D000077556:Alitretinoin; D014212:Tretinoin; D016572:Cyclosporine; D019821:Simvastatin; D007654:Ketoconazole