title: Use of a cocktail probe to assess potential drug interactions with cytochrome P450 after administration of belatacept, a costimulatory immunomodulator.
abstract: This open-label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers.
  
  
  
  Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4.
  
  
  
  Since belatacept caused no major alterations to cytokine levels, there were no major effects on CYP-substrate pharmacokinetics, except for a slight (16-30%) increase in omeprazole exposure, which was probably due to omeprazole-mediated, time-dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration -time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites.
  
  
  
  Therefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Daphne
authors.initials: D
authors.lastname: Williams
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.|Sandoz, Princeton, New Jersey, USA.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Tao
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Stonier
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.|Gilead Sciences Inc., Foster City, California, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lutz
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.|AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.|GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.|Rinat, South San Francisco, California, USA.
authors.forename: Bishu
authors.initials: B
authors.lastname: Ganguly
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Tzogas
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lubin
authors.affiliation: Bristol-Myers Squibb Research and Development, Pennington, New Jersey, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Murthy
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D010599:Pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D000069594:Abatacept; D003577:Cytochrome P-450 Enzyme System
keywords: Biologics; cytochrome P450; interaction; pharmacokinetics; transplantation