Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 57

Under inflammatory conditions, proinflammatory cytokines are produced locally around the pathological areas and are circulated to activate inflammatory responses in distal tissues (Wu and Lin, 2019). Cytokines like tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), interferon‐γ (IFN‐γ), and transforming growth factor‐β (TGF‐β) have been shown to reduce the expression of CYP1A2, CYP2C8, and CYP3A4 in cultured human hepatocytes. Given that CYP enzymes and drug transporters share certain common regulatory pathways, the effects of cytokines on the regulation of CYP enzymes may also be applicable to transporters (P‐gp). Aberrant expression of these drug‐processing proteins is observed in several animal models of human inflammatory diseases like type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders, and several neurodegenerative diseases. Cytokine‐induced gene regulation is probably driven by altered activities of various transcription factors, including nuclear factor‐κB (NF‐κB) and nuclear receptors. Thus, a therapeutic protein acting as a pro‐inflammatory cytokine or a cytokine modulator could potentially impact CYP enzyme and transporter function. There are still knowledge gaps in this area (13). TP–drug interactions have been evaluated from in vitro studies, animal studies, and/or clinical settings. An in vitro assessment of drug interaction between a small molecule and a cytokine could be initiated, if justified based on biology. Measuring cytokine levels in clinical study can provide supportive evidence for the DDI potential. FDA scientists (Jing et al., 2020) reported that about a third of the FDA‐approved drugs have TP labels that contain PK‐related DDI information derived from at least one study method. More than half of these evaluations showed no interaction, and for the remaining, no dose adjustment was recommended (Jing et al., 2020). For an antibody–drug conjugate (ADC), the interaction with small molecule drugs potentially involves not only the antibody component but also the small molecule drug component. However, since the free small molecule component may not be at high enough concentrations to act as a perpetrator; only the victim interaction must be evaluated. FDA has recently released a draft guidance to determine the need for DDI studies for a therapeutic protein (USFDA 2020c).