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Therapeutic Protein Drug Interaction Potential in Subjects With Psoriasis: An Assessment Based on Population Pharmacokinetic Analyses of Sensitive Cytochrome P450 Probe Substrates.
- Source :
-
Journal of clinical pharmacology [J Clin Pharmacol] 2021 Mar; Vol. 61 (3), pp. 307-318. Date of Electronic Publication: 2020 Sep 22. - Publication Year :
- 2021
-
Abstract
- Elevated cytokine levels in inflammatory diseases are associated with downregulation of certain cytochrome P450 (CYP) enzymes. Upon treatment with some cytokine-targeting therapeutic proteins, the CYP enzymes levels may be restored resulting in therapeutic protein-mediated drug interactions (TP-DI). These analyses characterized the worst-case scenario for CYP1A2, 2C9, and 3A-based TP-DI potential in patients with psoriasis by comparing the pharmacokinetics of probe substrates between healthy volunteers and subjects with moderate to severe psoriasis. Data for the CYP probe substrates midazolam (CYP3A), caffeine (CYP1A2), and S-warfarin (CYP2C9) from 7 drug interaction studies (1 in patients with psoriasis and 6 in healthy subjects) were pooled to develop a population pharmacokinetics model for each substrate. A 2-compartment model with absorption lag time for midazolam, a 1-compartment model with 5 transit absorption compartments for caffeine, and a 3-compartment model with absorption lag time for S-warfarin best described the observed data. Apparent oral clearance and relative bioavailability for caffeine and S-warfarin were not significantly different between the subject populations. Psoriasis patients were estimated to have 17% lower midazolam oral bioavailability than healthy volunteers. Compounded with other covariate effects, the ratio of median post hoc area under the plasma concentration-time estimates in subjects with psoriasis relative to healthy subjects was 0.96, 1.13, and 0.65 for midazolam, caffeine, and S-warfarin, respectively. Therefore, inflammation in psoriasis had no relevant effect on reducing CYP1A2, 2C9, and 3A activities in vivo and no significant TP-DIs mediated through these enzymes are expected in patients with psoriasis. This approach can potentially be used in lieu of dedicated TP-DI studies to identify TP-DI risks within a disease area.<br /> (© 2020, The American College of Clinical Pharmacology.)
- Subjects :
- Adult
Biological Availability
Caffeine pharmacokinetics
Case-Control Studies
Cytokines metabolism
Drug Interactions
Female
Humans
Male
Midazolam pharmacokinetics
Middle Aged
Patient Acuity
Warfarin pharmacokinetics
Young Adult
Cytochrome P-450 CYP1A2 metabolism
Cytochrome P-450 CYP2C9 metabolism
Cytochrome P-450 CYP3A metabolism
Models, Biological
Psoriasis physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4604
- Volume :
- 61
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32960975
- Full Text :
- https://doi.org/10.1002/jcph.1744