Disease–Drug Interactions in Inflammatory States via Effects on CYP‐Mediated Drug Clearance

Abstract

The human inflammatory response can result in the alteration of drug clearance through effects on drug-metabolizing enzymes or drug transporters. In this article, clinical examples are reviewed of how diseases with moderate to severe inflammation can decrease cytochrome P450 (CYP)-mediated drug clearance and alter plasma protein binding. Also examined is how albumin, α-1-acid glycoprotein, drug fraction unbound in plasma, CYP content, and oral clearance can change dynamically with time in response to inflammation.

Profiling of hepatic metabolizing enzymes and nuclear receptors in rats with adjuvant arthritis by targeted proteomics

“…Further studies are needed to clarify the detailed effects of decreased CAR and RXRα in AA rats on the induction of CYP and UGT protein expression. In humans, the pharmacokinetics of various drugs are found to be changed by inflammation and inflammatory disorders (Coutant & Hall, ; Cressman, Petrovic, & Piquette‐Miller, ; Kacevska, Robertson, Clarke, & Liddle, ; Renton, ). However, it is unclear whether the inflammation in AA rats raises similar concerns in humans.…”

Are Clinical Therapeutic Protein‐Drug Interaction Studies Needed When Disease Modification Is Driving the Potential Interaction?

“…Third, drug interactions mediated through disease/cytokine modification raise different considerations than other types of drug interactions. As pointed out by Coutant and Hall, the net effect of treatment in this case is reduced cytokine levels, leading to partial restoration of CYP enzyme and drug transporter activities, potentially resulting in mild reduction of victim drug exposures. As such, reduced efficacy, rather than toxicity, is the likely outcome.…”

“…We read with great interest the article by Coutant and Hall recently published in The Journal of Clinical Pharmacology regarding disease‐drug interactions in inflammatory states. This article provides a comprehensive review of the impact of inflammatory diseases on drug clearance via cytokine‐cytochrome P450 (CYP)‐mediated disease‐drug interactions, with a conclusion that in most cases inflammatory disease–drug interactions are not expected to be of clinical concern.…”

“…First, though comparisons of cytokine levels between patients and healthy subjects may be useful for understanding extreme differences in drug clearance between inflammatory disease and healthy status, such comparisons may overestimate the magnitude of difference in drug exposure caused by TP‐DIs mediated through disease/cytokine modulation by therapeutic proteins. In fact, most of the disease‐mediated TP‐DIs due to normalization/suppression of proinflammatory cytokines have shown at most only mild to moderate effects on drug exposures and have rarely led to a dose adjustment for the victim drug (AbbVie data on file for risankizumab and for other related TP‐DIs).…”

Drug Interaction Involving Direct or Indirect Cytokine Modulation Should Be Investigated in Select Circumstances

“…We concur that small‐molecule drugs have the same potential as TPs to cause indirect drug interactions through effective treatment of certain diseases with moderate to severe inflammation. This is evidenced in our article wherein there are several clinical examples that show that inflammatory diseases, irrespective of TP or small‐molecule drug treatment, can cause mild to moderate changes in CYP‐mediated clearance. We posit that inflammatory diseases themselves can cause indirect changes in CYP‐mediated drug clearance, and that it is not TP‐DDIs per se, but rather indirect DDIs with either small molecules or TPs that are worth evaluation.…”