Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform.
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Long TJ, Cosgrove PA, Dunn RT 2nd, Stolz DB, Hamadeh H, Afshari C, McBride H, Griffith LG
Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform.
Drug Metab Dispos. 2016 Dec;44(12):1940-1948. doi: 10.1124/dmd.116.071456. Epub 2016 Sep 12.
- PubMed ID
- 27621203 [ View in PubMed]
- Abstract
Traditional in vitro human liver cell culture models lose key hepatic functions such as metabolic activity during short-term culture. Advanced three-dimensional (3D) liver coculture platforms offer the potential for extended hepatocyte functionality and allow for the study of more complex biologic interactions, which can improve and refine human drug safety evaluations. Here, we use a perfusion flow 3D microreactor platform for the coculture of cryopreserved primary human hepatocytes and Kupffer cells to study the regulation of cytochrome P450 3A4 isoform (CYP3A4) activity by chronic interleukin 6 (IL-6)-mediated inflammation over 2 weeks. Hepatocyte cultures remained stable over 2 weeks, with consistent albumin production and basal IL-6 levels. Direct IL-6 stimulation that mimics an inflammatory state induced a dose-dependent suppression of CYP3A4 activity, an increase in C-reactive protein (CRP) secretion, and a decrease in shed soluble interleukin-6 receptor (IL-6R) levels, indicating expected hepatic IL-6 bioactivity. Tocilizumab, an anti-IL-6R monoclonal antibody used to treat rheumatoid arthritis, has been demonstrated clinically to impact small molecule drug pharmacokinetics by modulating cytochrome P450 enzyme activities, an effect not observed in traditional hepatic cultures. We have now recapitulated the clinical observation in a 3D bioreactor system. Tocilizumab was shown to desuppress CYP3A4 activity while reducing the CRP concentration after 72 hours in the continued presence of IL-6. This change in CYP3A4 activity decreased the half-life and area under the curve up to the last measurable concentration (AUClast) of the small molecule CYP3A4 substrate simvastatin hydroxy acid, measured before and after tocilizumab treatment. We conclude that next-generation in vitro liver culture platforms are well suited for these types of long-term treatment studies and show promise for improved drug safety assessment.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Tocilizumab Cytochrome P450 3A4 Protein Humans NoInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareApremilastUstekinumab The therapeutic efficacy of Apremilast can be decreased when used in combination with Ustekinumab. ApremilastAbatacept The therapeutic efficacy of Apremilast can be decreased when used in combination with Abatacept. ApremilastAdalimumab The therapeutic efficacy of Apremilast can be decreased when used in combination with Adalimumab. ApremilastAnakinra The therapeutic efficacy of Apremilast can be decreased when used in combination with Anakinra. ApremilastCertolizumab pegol The therapeutic efficacy of Apremilast can be decreased when used in combination with Certolizumab pegol.