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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

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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 100 pg/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.

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Acknowledgments

The authors thank Certara’s library team for their assistance in the preparation and submission of this paper. The authors thank Hajime Ito for his assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. Certara UK Limited, Simcyp Division, Sheffield, UK

    Krishna K. Machavaram, Katherine L. Gill, Oliver J. Hatley & Iain Gardner

  2. Clinical Pharmacology Department, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan

    Chihiro Endo-Tsukude & Kimio Terao

  3. Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland

    Neil Parrott & Patricia Sanwald Ducray

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  1. Krishna K. Machavaram
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Contributions

K.K.M., C.E.-T., K.T., K.L.G., O.J.H., I.G., N.P., and P.S.D. wrote the manuscript.

K.K.M., C.E.-T., K.L.G., I.G., N.P., and P.S.D. designed the research.

K.K.M., K.L.G., O.J.H., and I.G. performed the research.

K.K.M., K.L.G., and I.G. analyzed the research.

Corresponding author

Correspondence to Krishna K. Machavaram.

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Conflict of Interest

K.K.M., K.L.G., and I.G. are employees of Certara UK Limited, Simcyp Division, Sheffield, United Kingdom.

C.E.-T. and K.T. are employees of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

N.P. and P.S.D. are employees of F. Hoffmann–La Roche Ltd., Basel, Switzerland.

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Machavaram, K.K., Endo-Tsukude, C., Terao, K. et al. 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. AAPS J 21, 42 (2019). https://doi.org/10.1208/s12248-019-0309-y

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