Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

Abstract

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100pg/mL). Moderate interactions [mean AUC fold change, ≤ 2.08 (midazolam) or 2.36 (simvastatin)] was predicted for CYP3A4 probe substrates and weak interactions (mean AUC fold change, ≤ 1.29-1.97) were predicted for CYP2C19, CYP2C9, and CYP2D6 substrates. No notable interaction was predicted with CYP1A2. Although ethnic differences led to differences in simulated exposure for some of the probe substrates, there were no marked differences in the predicted magnitude of the change in exposure following IL-6-mediated suppression of CYPs. Decreased levels of serum albumin (as reported in NMO patients) had little impact on the magnitude of the simulated IL-6-mediated drug interactions. This PBPK modeling approach allowed us to leverage knowledge from different disease and ethnic populations to make predictions of cytokine-related DDIs in a rare disease population where actual clinical studies would otherwise be difficult to conduct.