title: The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers.
abstract: OBJECTIVE
  Two clinical studies were conducted to determine possible drug-drug interactions between apremilast and a strong CYP3A4 inhibitor, ketoconazole, or a potent CYP3A4 inducer, rifampicin. The main objectives of these two studies were to evaluate the impact of multiple doses of ketoconazole on the pharmacokinetics of apremilast and its metabolites, and the effect of multiple oral doses of rifampicin on the pharmacokinetics of apremilast.
  
  
  METHODS
  These single centre, open label, sequential treatment studies in healthy subjects included two treatment periods for ketoconazole and three treatment periods for rifampicin. Apremilast was administered as a 20 mg (ketoconazole study) or 30 mg (rifampicin study) single oral dose.
  
  
  RESULTS
  Ketoconazole increases overall exposure (AUC(0,∞)) of apremilast by ≈36% (2827 vs. 2072 ng ml(-1)  h, 90% CI = 126.2, 147.5) and peak exposure (Cmax ) by 5% (247 vs. 236 ng ml(-1) ). Multiple doses of rifampicin increase apremilast clearance ≈3.6-fold and decrease apremilast mean AUC(0,∞) by ≈72% (3120 vs. 869 ng ml(-1)  h, 90% CI = 25.7, 30.4) and Cmax (from 290 vs. 166 ng ml(-1) ) relative to that of apremilast given alone. A 30 min intravenous infusion of rifampicin 600 mg had negligible effects on the overall exposure (AUC(0,∞)) of apremilast (2980 vs. 3120 ng ml(-1)  h, 90% CI = 88.0, 104.1).
  
  
  CONCLUSIONS
  Ketoconazole slightly decreased apremilast clearance, resulting in a small increase in AUC which is probably not meaningful clinically. However, the effect of CYP3A4 induction by rifampicin on apremilast clearance is much more pronounced than that of CYP3A4 inhibition by ketoconazole. Strong CYP3A4 inducers may result in a loss of efficacy of apremilast because of decreased drug exposure.
authors: Celgene Corporation, Summit, New Jersey, USA.
authors: Yong
authors: Y
authors: Liu
authors: Simon
authors: S
authors: Zhou
authors: Yuntao
authors: Y
authors: Wan
authors: Anfan
authors: A
authors: Wu
authors: Maria
authors: M
authors: Palmisano
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002352:Carrier Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D013379:Substrate Specificity; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D058988:Phosphodiesterase 4 Inhibitors; D013792:Thalidomide; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole; C505730:apremilast; D012293:Rifampin
keywords: drug interaction; inflammatory autoimmune disorders; phosphodiesterase 4 inhibitor