J. Q. Tran,1 A. A. Othman,2 A. Mikulskis,1 Y. Wu,1 P. Wolstencroft,1 J. Elkins1; 1Biogen Idec, Cambridge, MA, 2AbbVie, Chicago, IL

BACKGROUND: Daclizumab high yield process (DAC HYP) is an anti-interleukin-2 (IL-2) receptor monoclonal antibody being developed for treatment of multiple sclerosis (MS). Since DAC HYP treatment results in a detectable increase in serum IL-2 levels and changes in cytokine levels may influence expression of the cytochrome P450 (CYP) isoenzymes, a clinical study was conducted to evaluate the effect of DAC HYP on CYP activities.
METHODS: Twenty subjects with MS received an oral cocktail of probe substrates of CYP3A (midazolam 5 mg), CYP2C9 (warfarin 10 mg / vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP1A2 (caffeine 200 mg) and CYP2D6 (dextromethorphan 30 mg) at 2 sequential occasions: 7 days before and 7 days after administration of DAC HYP 150 mg SC every 4 weeks for 3 doses. Serial PK blood samples up to 96 hours and 12-hour urine samples were collected in both occasions. The AUC for midazolam, caffeine, S-warfarin, and omeprazole and the urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model.
RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for midazolam AUCinf (0.89 - 1.15), omeprazole AUCinf (0.88 - 1.13), S-warfarin AUCinf (0.95- 1.06), and caffeine AUC0-12 (0.93 - 1.15) were within the no-effect boundary of 0.80 - 1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01; with the 90% CI (0.76 - 1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity.
CONCLUSION: DAC HYP treatment in MS patients had no effect on CYPs 1A2, 2C9, 2C19, 2D6, and 3A activities.