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

Abstract

Dear Editor, We read with great interest the article by Coutant and Hall1 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. The information in this article raises some important questions regarding therapeutic protein–drug interaction (TP-DI) assessments for therapeutic proteins being developed for the treatment of inflammatory diseases. This topic is of particular interest given that the updated 2017 Food and Drug Administration guidance2 does not include discussion on therapeutic proteins and that the Food and Drug Administration is currently seeking public comments on the optimal regulatory framework in which to assess TP-DIs.3 We would like to point out several key items that should be taken into consideration when evaluating the TP-DI potential for therapies targeting proinflammatory cytokines. 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,1 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-DIs4-8). Second, dedicated TP-DI studies are typically conducted in patients, without the full course of the proposed therapeutic protein treatment for therapeutic benefit and disease modification. Such studies put patients at risk for developing antidrug antibodies, which could negatively affect future treatment. Therefore, the scientific benefit gained from conducting TP-DI studies does not necessarily outweigh the risks. Third, drug interactions mediated through disease/cytokine modification raise different considerations than other types of drug interactions. As pointed out by Coutant and Hall,1 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. There are only a few sensitive CYP substrates with a narrow therapeutic index for which a small change in exposure would fall outside the desired therapeutic range, and these should be closely monitored anyway. Fourth, similar to therapeutic proteins, small-molecule drugs have the same potential to cause drug interactions if they reduce cytokine levels via disease modification, yet such assessments for small-molecule drugs are neither performed nor required by regulatory guidelines, indicating the lack of necessity or clinical relevance of such evaluations. The ultimate goal of drug interaction studies is to determine the magnitude of change in drug exposure that can be expected clinically so that labeling can be put into place. However, based on the points discussed above, when changes in drug exposure are driven by disease modification, conventional drug interaction studies are often not clinically informative. It is our opinion that dedicated TP-DI studies are generally not needed, especially for the following 2 scenarios: (1) For new therapeutic proteins that target pathways previously studied for other therapeutic proteins, TP-DI studies are not needed if the previously studied therapeutic protein has demonstrated little or no TP-DI potential; and (2) if a therapeutic protein is being developed for multiple indications and the therapeutic protein has been shown to have little or no TP-DI potential in the disease with the most severe inflammatory burden, TP-DI studies are not needed in any new indications that have a less severe inflammatory burden. For a novel target pathway, data on cytokines that have known effects on CYPs or transporters can be collected before and after therapeutic protein treatment in phase 2/3 studies to guide the TP-DI risk assessment, and, if needed, a TP-DI substudy can be incorporated into the phase 2/3 studies to evaluate the impact of the therapeutic protein on narrow therapeutic index drugs. We believe that continuing to default to dedicated TP-DI studies for therapeutic proteins targeting inflammatory diseases is not supported by available scientific evidence, and drug development standards need to be revised accordingly. The authors are employees and shareholders of AbbVie.