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.

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

“…CYP3A4 activity assays were run after sampling on days 9 and 14. Inflammation-Mediated DDI in 3D Liver Bioreactor in the clinical range for inflammatory diseases (10-1500 pg/ml; Machavaram et al, 2013), as did the 1 ng/ml IL-6 dose subsequently chosen for chronic inflammation studies.…”

Critical Review of Preclinical Approaches to Investigate Cytochrome P450–Mediated Therapeutic Protein Drug-Drug Interactions and Recommendations for Best Practices: A White Paper

“…These minimally include TP pharmacology and clearance pathways, a thorough understanding of relevant cytokines and their impact on cytochrome P450 enzymes in the disease setting, the patient population, and comedications. Physiologybased PK/pharmacodynamics (PD) modeling has been used in retrospective attempts to relate in vitro IL-6 effects on CYP3A4 to the clinical tocilizumab:simvastatin interaction and to SMD clearance in organ transplant and surgical trauma (Machavaram et al, 2013). Unfortunately, IL-6 is currently the only cytokine-mediated TP-DDI for which both in vitro and in vivo data are available.…”

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

“…Simulated steady-state IL-6 concentrations were then linked to effects on multiple hepatic CYP enzyme levels, and new steady-state (SS) levels of hepatic CYP enzymes were achieved over the simulation period (depending on the setting of turnover rate of each individual CYP enzyme within Simcyp, 90% of SS was reached between 7 and 19 days after continuous exposure to IL-6). The suppressive effect of IL-6 on intestinal CYP enzymes was assumed to be the same as that on hepatic CYPs, and the intestinal CYP enzyme levels were manually modified in the virtual RA patient population (13,29,30). For each individual intestinal CYP enzyme, the remaining enzyme activity was calculated with the log (inhibitor/agonist) versus response model (details presented in BModeling of Enzyme Dynamics^section) with the enzyme inhibition/induction information obtained from in vitro enzyme regulation studies (Table I).…”

“…The systemic IL-6 concentration used in the current PBPK model was simulated with the following model inputs, which are adopted from a recently published IL-6 PBPK model with modification (13): molecule weight = 21,000 g/ mol systemic clearance (CLi.v.) = 1.0 L/h and volume of distribution at steady state (Vss) = 0.43 L/kg.…”

“…Due to the comprehensive array of drug-independent system features, PBPK modeling may offer researchers an a priori approach to predict a compound's pharmacokinetic (PK) behavior under a variety of clinical circumstances, such as variability in age, disease, and genetics, with prior knowledge of the biological system and the drug substance's physicochemical characteristics (11,12). A recently published PBPK model successfully demonstrated the impact of IL-6 and the therapeutic effect of tocilizumab on CYP3A4 activity in RA patients by characterizing the changes of PK of CYP3A4 substrate simvastatin in RA virtual patients before and after treatment (13), suggesting the potential of PBPK modeling in describing the impact of RA disease and anti-IL-6 therapy on CYP enzyme activity as well as the associated changes in drug exposure.…”