Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

Abstract

Abstract. Disease-mediated therapeutic protein-drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients.

Prediction of Atorvastatin Pharmacokinetics in High-Fat Diet and Low-Dose Streptozotocin-Induced Diabetic Rats Using a Semiphysiologically Based Pharmacokinetic Model Involving Both Enzymes and Transporters

“…Recently, a PBPK model involving both enzyme and drug transporter turnover has been used to predict the disposition of drugs successfully (Rasool et al, 2015;Jiang et al, 2016;Ono et al, 2017;Hsueh et al, 2018) under disease status, including diabetes or drug-drug interactions (Guo et al, 2013;Wang et al, 2013;Ono et al, 2017). The present study demonstrated that diabetes significantly altered the expression and the function of intestinal or hepatic CYP3a1, P-gp, BCRP, and OAPTs in a different manner.…”

Current trends in drug metabolism and pharmacokinetics

“…Similarly, by triggering inflammation, influenza vaccination has been reported to decrease CYP activity and thus influence the systemic exposure of CYP substrates such as clozapine 168 . PBPK modeling is a powerful tool for the investigation of pharmacokinetic-based interactions between therapeutic biologics and small molecules, and has been successfully applied to quantitatively predict DDIs of CYP-modulating protein drugs (such as blinatumomab and sirukumab) and small molecule CYP substrates in patients 169 , 170 . On the other hand, pharmacokinetic interaction between two therapeutic biologics has seldom been reported.…”

The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

“…This hypothesis has been validated for TPs targeting the IL-6 pathway in patients with rheumatoid arthritis. Indeed, the mAbs tocilizumab and sarilumab, directed against the IL-6 receptor a, as well as the IL-6-neutralizing mAb sirukumab, reduce exposure of coadministrated drugs like simvastatin, midazolam, or omeprazole (Schmitt et al, 2011;Zhuang et al, 2015;Lee et al, 2017), most probably through reversal of IL-6-mediated suppression of P450 expression (Jiang et al, 2016).…”