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Background Upadacitinib is a selective Janus kinase 1 inhibitor, which is approved for treatment of several inflammatory diseases. Upadacitinib 45 mg QD dose was evaluated for induction treatment in ulcerative colitis Phase 3 studies and is currently being evaluated in Crohn’s disease Phase 3 studies. A prior clinical study demonstrated that upadacitinib 30 mg QD dose resulted in no clinically relevant effects on plasma exposures of sensitive probe substrates for cytochrome P450 (CYP) enzymes. The objective of this study was to evaluate the effect of repeated doses of upadacitinib 45 mg on the pharmacokinetics of sensitive probe substrates of CYP enzymes in healthy adult subjects. Methods This was an open-label, multiple-dose, two-period study using the modified Cooperstown 5 + 1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]). Twenty healthy adults received single oral doses of the cocktail drugs without upadacitinib in Period 1, followed by daily dosing of upadacitinib 45 mg for 16 days and administration of the cocktail drugs on Day 11 (for midazolam) and Day 12 (rest of substrates) in Period 2. A washout period of 6 days separated each Period. Serial blood samples and 12-hour urine samples (for dextromethorphan and dextrorphan) were collected. Pharmacokinetic parameters were estimated using noncompartmental analysis and repeated-measures analyses were performed for the natural logarithms of Cmax and AUC to assess the effect of upadacitinib on the probe substrates. Results The ratio (90% confidence interval) of area under the plasma concentration-time curve from time 0 to infinity (AUCinf) central values when the cocktail drugs were administered with upadacitinib 45 mg relative to when administered alone were 0.76 (0.69–0.83) for midazolam, 1.04 (0.95–1.13) for caffeine, 1.12 (1.05–1.20) for S-warfarin, 1.35 (1.18–1.54) for dextromethorphan, and 0.98 (0.85–1.13) for omeprazole. The 5-hydroxy-omeprazole to omeprazole plasma AUC ratio was unchanged (90% confidence interval within the no effect limits of 0.8 to 1.25). Conclusion Administration of daily upadacitinib 45 mg doses resulted in a limited effect on midazolam (CYP3A) and dextromethorphan (CYP2D6) exposures and had no relevant effects on the sensitive probe substrates for CYP1A2, CYP2C9 and CYP2C19. These limited effects are not expected to be clinically relevant or necessitate dose adjustment of CYP3A or CYP2D6 substrates. These results are consistent with a previous drug interaction evaluation for upadacitinib 30 mg and support lack of relevant effects of upadacitinib on drugs metabolized by CYP enzymes.

P556 The effect of multiple doses of upadacitinib 45 mg on the pharmacokinetics of cytochrome P450 substrates in healthy adult subjects