title: Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects.
abstract: OBJECTIVE
  To investigate the effect of co-administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5-hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5-hydroxy saxagliptin, its major pharmacologically active metabolite.
  
  
  METHODS
  In a non-randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady-state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5-hydroxy saxagliptin) and PD (plasma DPP-4 activity) were measured for up to 24 h on days 1 and 7.
  
  
  RESULTS
  Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean C(max) and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean C(max) and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5-hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition-time effect curve over 24 h for DPP-4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated.
  
  
  CONCLUSIONS
  Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co-administered with rifampicin.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Global Biometric Sciences, Bristol-Myers Squibb Company and Pharmaceutical Candidate Optimization, Biotransformation, Bristol-Myers Squibb Company, Princeton, NJ 08543, USA. vijay.upreti@bms.com
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Upreti
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Agatha
authors.initials: A
authors.lastname: Ching
authors.forename: Hong
authors.initials: H
authors.lastname: Su
authors.forename: Frank P
authors.initials: FP
authors.lastname: Lacreta
authors.forename: Chirag G
authors.initials: CG
authors.lastname: Patel
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D019540:Area Under Curve; D004151:Dipeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane; D012293:Rifampin