title: A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6.
abstract: Elevated cytokine levels are known to downregulate expression and suppress activity of cytochrome P450 enzymes (CYPs). Cytokine-modulating therapeutic proteins (TPs) used in the treatment of inflammation or infection could reverse suppression, manifesting as TP-drug-drug interactions (TP-DDIs). A physiologically based pharmacokinetic model was used to quantitatively predict the impact of interleukin-6 (IL-6) on sensitive CYP3A4 substrates. Elevated simvastatin area under the plasma concentration-time curve (AUC) in virtual rheumatoid arthritis (RA) patients, following 100 pg/ml of IL-6, was comparable to observed clinical data (59 vs. 58%). In virtual bone marrow transplant (BMT) patients, 500 pg/ml of IL-6 resulted in an increase in cyclosporine AUC, also in good agreement with the observed data (45 vs. 39%). In a different group of BMT patients treated with cyclosporine, the magnitude of interaction with IL-6 was underpredicted by threefold. The complexity of TP-DDIs highlights underlying pathophysiological factors to be considered, but these simulations provide valuable first steps toward predicting TP-DDI risk.
authors.affiliation: Simcyp (a Certara Company), Sheffield, UK.
authors.forename: K K
authors.initials: KK
authors.lastname: Machavaram
authors.forename: L M
authors.initials: LM
authors.lastname: Almond
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: I
authors.initials: I
authors.lastname: Gardner
authors.forename: M
authors.initials: M
authors.lastname: Jamei
authors.forename: S
authors.initials: S
authors.lastname: Tay
authors.forename: S
authors.initials: S
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.forename: J R
authors.initials: JR
authors.lastname: Kenny
mesh_terms: D000924:Anticholesteremic Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D003198:Computer Simulation; D016572:Cyclosporine / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D015850:Interleukin-6 / Q000494:pharmacology*; D008954:Models, Biological; D019821:Simvastatin / Q000493:pharmacokinetics
chemical_list: D000924:Anticholesteremic Agents; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016572:Cyclosporine; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A