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Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail
Author(s) -
Mohamed MohamedEslam F.,
Feng Tian,
Enejosa Jeffrey V.,
Fisniku Ogert,
Othman Ahmed A.
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1496
Subject(s) - dextromethorphan , omeprazole , pharmacology , dextrorphan , pharmacokinetics , cyp3a , chemistry , cyp1a2 , cyp2c19 , midazolam , drug interaction , cytochrome p450 , medicine , sedation , enzyme , biochemistry
The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15‐day regimen of upadacitinib 30 mg once daily (extended‐release formulation). Serial blood samples and 12‐hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration‐time curve from time 0 to infinity (AUC inf ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68‐0.80) for midazolam, 1.22 (1.15‐1.29) for caffeine, 1.11 (1.07‐1.15) for S‐warfarin, 1.07 (0.95‐1.22) for dextromethorphan, and 0.82 (0.72‐0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00‐1.19) for 5‐hydroxy‐omeprazole to omeprazole AUC inf ratio and 1.17 (0.97‐1.41) for dextromethorphan to dextrorphan 12‐hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.