Purpose: To assess the effects of belatacept (bela) on the pharmacokinetics (PK) of orally administered caffeine, midazolam, losartan, omeprazole, and dextromethorphan (Inje cocktail) as probe substrates for CYP1A2, 3A4, 2C9, 2C19, and 2D6, respectively. Method: Open-label, single-sequence study in healthy subjects (N=22). On day 1, subjects received a single oral dose of the Inje cocktail. On day 4, subjects received a single 10-mg/kg infusion of bela over 30 minutes and the Inje cocktail. To evaluate the potential modulation of cytokine levels by bela and subsequent effects on CYP activity and PK of substrates, subjects also received a single dose of the Inje cocktail on days 7 and 11, and cytokine levels were assessed on days -1, 1, 4, 7, 11, 18, 32, and 46. Serial blood samples were taken on days 1, 4, 7, and 11 to determine PK parameters, including the maximum concentration (Cmax) and the area under concentration curve to infinity (AUC), of substrates and metabolites. Result: ·Cmax and AUC adjusted geometric mean ratio (GMR) on days 4, 7, and 11 vs day 1 for caffeine and midazolam were close to 1 and the 90% confidence intervals (CI) were all within 0.80 to 1.25. ·AUC adjusted GMR on days 4, 7, and 11 vs day 1 for losartan were close to 1 and the 90% CIs were within 0.80 to 1.25. The upper boundary of 90% CI of Cmax was marginally above 1.25, perhaps due to large variability. ·Cmax and AUC of omeprazole were 16% to 30% greater on days 4, 7, and 11 vs day 1. A simulation using SimCYP demonstrated that dosing omeprazole alone on days 1, 4, 7, and 11 could result in 20-30% accumulation, suggesting the increase of omeprazole exposure may be bela-independent. ·The 90% CIs of AUC ratios on days 7 and 11 vs day 1 of dextromethorphan were within 0.80 to 1.25. On day 4, the AUC ratio was slightly lower than 1, and the lower bound of the 90% CIs of Cmax were slightly below 0.80, possibly due to large variability. ·Cytokines (TNF-α, IFN-α, IFN-γ, IL-2, IL-6, and IL-10) showed no significant change after the administration of bela on all assessment days. Conclusion: Belatacept had no effect on the PK of caffeine (CYP1A2), midazolam (CYP3A), losartan (CYP2C9), or dextromethorphan (CYP2D6). Omeprazole (CYP2C19) exposure was slightly increased but not considered clinically significant. This increase is likely due to inhibition of its own CYP2C19-mediated metabolism by omeprazole. DISCLOSURES:Tao, X.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb. Zhu, L.: Employee, Bristol-Myers Squibb. Stonier, M.: Employee, Bristol-Myers Squibb. Zhang, S.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb. Ganguly, B.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb. Tzogas, Z.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb. Lubin, S.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb. Masson, E.: Employee, Bristol-Myers Squibb, Stockholder, Bristol-Myers Squibb.