08/26/2024
Imagine an elderly patient with lipoproteinemia who has been stabilized on simvastatin for years. Let’s say this patient also has rheumatoid arthritis that has failed to respond to NSAIDs. One week after receiving a single 200 mg subcutaneous dose of a drug for arthritis, her plasma concentration of simvastatin is found to be markedly decreased. Which anti-arthritis medication could have caused this phenomenon?
You already know that simvastatin is a substrate of CYP450 3A4 and OATP 1B1. What may be difficult to understand is that plasma concentrations of drugs that are CYP450 substrates may decrease following the initiation of interleukin (IL) inhibitors, tumor necrosis factor (TNF) blockers, or interferon (IFN) inhibitors in patients with chronic inflammatory diseases, such as rheumatoid arthritis.
Normally, the formation of hepatic CYP450 enzymes is down-regulated during infection and chronic inflammation by increased levels of certain cytokines (e.g., interleukins-1, -6, and -10; tumor necrosis factor alpha; interferons). Consequently, treatment targeting these cytokines may restore or normalize CYP450 enzyme levels resulting in increased metabolism of these drugs.
Simvastatin systemic exposure is decreased by 45% by a single dose of sarilumab, an IL-6 inhibitor, in rheumatoid arthritis patients.
In fact, tocilizumab, another IL-6 inhibitor, has been found to impact expression of various CYP enzymes including CYP450 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.
Because no role for other interleukins such as IL-12, IL-17A, or IL-23 in the regulation of CYP450 enzymes has been established, risankizumab and tildrakizumab, both IL-23 antagonists, should not be answers to pick on the USMLE regarding this specific concept. This does not mean that risankizumab and tildrakizumab won’t be tested in other capacities; there are always questions testing their dermatologic applications and immunophysiologic mechanisms. But with regards to USMLE questions relating to hepatic microsomal enzymes and drug metabolism, always go with IL-1, IL-6, and IL-10 modulators (No IL-10 modulators are clinically available currently, so that leaves only IL-6 and IL-10).
Now, besides sarilumab and tocilizumab, which other IL-6 modulators can you name?