Modelling the Effect of Interleukin-6, an Inflammatory Cytokine, on Time-dependent Reduction of Cyclosporine Clearance: An Application of the Simcyp Population-based Simulator to Suppression of CYP450 by Biologics
Krishna K Machavaram (1), Lisa M Almond (1), Masoud Jamei (1) and Amin Rostami-Hodjegan (1&2)
(1) Simcyp Limited, Sheffield, United Kingdom; (2) CAPKR, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, United Kingdom
Objectives: Modelling the effect of interleukin-6 (IL-6) on the pharmacokinetics (PK) of cyclosporine in virtual bone marrow transplant patients and comparing predictions with the observed data (Chen et al., 1994) to assess the possibility of in vitro in vivo extrapolation (IVIVE).
Methods: The serum IL-6 levels from two representative patients were fitted with appropriate PK models. These models were used to simulate the serum profile of IL-6 in virtual patients within Simcyp (Version 10, Service Pack 1). The effect of IL-6 was investigated on the cyclosporine PK following intravenous administration. The study design was consistent with that of reported clinical investigation.
Results: A zero order input rate and first order elimination, adequately recovered the clinically reported endogenous IL-6 profiles in patients. The linked model predicted a marked increase in systemic cyclosporine levels in the presence of IL-6, consistent with its suppression of CYPs. The IVIVE-generated pattern in time-varying systemic cyclosporine levels was broadly comparable with the observed data (Chen et al., 1994). The simulated results suggested the possibility of predicting suppression effects on CYPs by biologics/therapeutic proteins acting via IL-6 or in similar fashion to that of IL-6 (i.e. suppression of CYP3A4 enzyme; Aitken and Morgan, 2007). The observed high inter-individual variability in IL-6 profiles in patients (Chen et al., 1994) as well as possible involvement of other factors such as C-reactive protein and variable levels of α1-acid glycoprotein might have an impact on the magnitude of prediction. These factors were not considered in the current model. Nonetheless, these preliminary results are encouraging for further investigation into IVIVE of CYP-mediated effects by therapeutic proteins on reducing the clearance of smaller drug molecules.
Conclusions: Application of a novel Simcyp module was successful in demonstrating predictability of the effect of IL-6 on cyclosporine PK in patients with elevated levels of IL-6. The simulations pave the way for extrapolating the in vitro information on CYP-mediated drug-drug interactions involving biologics.
 Chen YL et al., Clinical Pharmacology and Therapeutics 1994, 55, 649-60
 Aitken AE and Morgan ET. Drug Metabolism and Disposition 2007, 35, 1687-93