Therapeutic Protein Drug Interaction Potential in Subjects With Psoriasis: An Assessment Based on Population Pharmacokinetic Analyses of Sensitive Cytochrome P450 Probe Substrates.

Therapeutic Protein Drug Interaction Potential in Subjects With Psoriasis: An Assessment Based on Population Pharmacokinetic Analyses of Sensitive Cytochrome P450 Probe Substrates. J Clin Pharmacol. 2020 Sep 22;: Authors: Sathe AG, Othman AA, Mohamed MF 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 pop...
Source: The Journal of Clinical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: J Clin Pharmacol Source Type: research