Interleukin-6 and cytochrome-P450, reason for concern?

Abstract

Interleukin 6 (IL-6) plays a central role in the immunopathogenesis of rheumatoid arthritis (RA) and tocilizumab [TCZ] (an anti-IL-6 receptor antibody) has been shown to be effective in the treatment of the condition. As up-regulation of IL-6 reduces the activity of cytochrome P450 (CYP) enzymes, blockade of this cytokine may enhance CYP function. This may lead to reduced bioavailability of CYP-metabolized drugs. Due to the increasing use of TCZ, we undertook a systematic literature review to explore such interactions. Our search was conducted in MEDLINE, EMBASE, Web of Science, FDA and EMEA websites for in vitro and in vivo studies, clinical trials and reviews mentioning TCZ and CYP on the basis of the title and abstract. Appropriate articles were further screened based on full-text review to select only those reporting IL-6, TCZ and their potential interaction with CYP-metabolized drugs. Two in vitro studies showed that TCZ-reversed IL-6 induced reduction of CYP isozymes. CYP3A4 mRNA expression was most reduced by IL-6 followed by CYP2C9 and CYP2C19. This change was prevented with TCZ. Three clinical studies investigated the interaction showing simvastatin (CYP3A4 substrate) bioavailability reduced by TCZ and omeprazole bioavailability was decreased by TCZ-induced CYP2C19 activity. The bioavailability of dextromethorphan (CYP2D6 and CYP3A4 substrates) was shown to be unaffected by TCZ treatment. The observed increase in CYP isozyme activity by TCZ is of clinical relevance as the bioavailability of the CYP isozyme substrates were decreased in vivo. As CYP3A4 is the isozyme responsible for the largest proportion of drug metabolism, it is probable that the bioavailability of other drugs may be reduced by TCZ. Thus, clinicians should exercise caution when co-prescribing TCZ and CYP-metabolized drugs. More studies are required to investigate this interaction further.

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (April 2020)

“…Tocilizumab is not metabolized by the cytochrome P450 isoenzyme system, however elevated IL-6 levels seen in inflammatory states have been shown to inhibit these enzymes, thereby slowing the metabolism of drugs through these pathways. As the 3A4 pathway is responsible for metabolism of many commonly used medications, administration of IL-6 inhibitors like tocilizumab may result in enhanced metabolism in drugs utilizing the cytochrome P450 system [34,35].…”

Role of Cytochrome P450s in Inflammation

“…On day 43, the AUC was 61% and trending toward baseline values. There were smaller effects of tocilizumab on other CYP-metabolized drugs (Kim, Ostor, & Nisar, 2012).…”

Optimizing Patient Outcomes with PD‐1/PD‐L1 Immune Checkpoint Inhibitors for the First‐Line Treatment of Advanced Non–Small Cell Lung Cancer

“…Moreover, traditional drug interaction studies and washout periods are often not adequate to fully assess mAbs due to their long half‐lives (weeks to months) . Although mAbs are not metabolized by hepatic enzymes such as cytochrome P450 (CYP), ICIs can stimulate the release of cytokines (e.g., interleukin [IL]‐6) that can decrease the enzyme activity of CYP3A4, CYP2C9, and CYP2C19 . Theoretically, this could lead to drug interactions with small molecules metabolized by these CYP pathways, resulting in higher bioavailability of the drug substrate and increased risk of drug toxicity.…”

“…57 Although mAbs are not metabolized by hepatic enzymes such as cytochrome P450 (CYP), 57 ICIs can stimulate the release of cytokines (e.g., interleukin [IL]-6) that can decrease the enzyme activity of CYP3A4, CYP2C9, and CYP2C19. 58 Theoretically, this could lead to drug interactions with small molecules metabolized by these CYP pathways, resulting in higher bioavailability of the drug substrate and increased risk of drug toxicity. A phase I trial was conducted to assess PK interactions between ipilimumab and dacarbazine or carboplatin/paclitaxel chemotherapy used for melanoma.…”