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

We concur with the response (commentary) from Pang et al that in most cases therapeutic drug-disease interactions (TP-DDIs) caused by inflammation are not of clinical concern. Indeed, recent data suggest that inflammatory disease states withmild inflammation, such asmultiple sclerosis1 and psoriasis,2 do not causemeaningful TP-DDIs involving cytochrome P450 (CYP) substrates. We also concur that once a lack of drug interaction is robustly demonstrated in a particular disease state (eg, psoriasis), there is no need to conduct additional TP-DDI studies in that disease state. There are only a few inflammatory disease states wherein drug monitoring would be advised, and then primarily when coadministering CYP-sensitive index substrates with a narrow therapeutic index. For instance, there are clinical data that suggest moderate to severe rheumatoid arthritis3,4 and Crohn disease5 can cause a 2-fold change in the clearance and exposure of CYP3A-sensitive substrates. The comment was made in the Letter to the Editor that “ . . . most of the disease-mediated TP-DDIs due to normalization/suppression of proinflammatory cytokines have shown only mild to moderate effects on drug exposures and have rarely led to dose adjustment for the victim drug.” This statement is true if considering patients with only minor systemic inflammation. Psoriasis, hepatitis C, and congestive heart failure are all diseases with negligible to mild effects on CYP-mediated clearance. The magnitude of TP-DI is related to both severity and type of inflammatory disease. Thus, an assessment of TP-DDI potential in patients with rheumatoid arthritis with mild systemic inflammation is expected to give an attenuated response compared to an assessment in patients with moderate to severe rheumatoid arthritis. The authors therefore recommend that 2 or more markers of inflammation (such as interleukin-6, C-reactive protein, albumin, α1-acid glycoprotein) be measured at the beginning and end of any inflammatory TP-DDI trial. In instances where only a mild effect onCYP-mediated clearancewas observed by a cytokine modulator, some of these TP-DDI trials either lacked an assessment of inflammatory markers or the markers Figure 1. Proposed flow scheme for evaluation of drug interactions caused by direct or indirect cytokine modulation.