August 2018

Response to FDA Framework for Assessment of Drug-Drug Interactions for Therapeutic Proteins RFI and Comments

Author:  Michael Millhollen
Posted:  06 August 2018

In July, Drs. Maciej Czerwinski, Director of Consulting, and Brian Ogilvie, Vice President of Scientific Consulting, submitted Sekisui XenoTech’s comments in response to the Food and Drug Administration (FDA) public docket to assist with its development of a policy/guidance document on the assessment of drug-drug interactions (DDIs) for therapeutic proteins (TPs).
 
The FDA’s 2017 DDI draft guidance documents, “In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies” and “Clinical Drug Interaction Studies—Study Design, Data Analysis, and Clinical Implications,” focused on enzyme- and transporter-based DDIs and did not include TPs. Therefore, the FDA is reviewing the draft 2012 DDI guidance framework for assessment of DDIs for TPs and requested input to assist in updating or creating a new framework.
 
From Sekisui XenoTech’s response: “We would like to contribute to the guidance development by highlighting a useful in vitro approach in response to question 2.a: What types of assessments can be useful (e.g., in vitro studies, dedicated clinical studies, population pharmacokinetic analyses, physiologically based pharmacokinetic analyses)?

  1. We agree that a therapeutic proteins' (TP), or more broadly a biologics', DDI perpetrator potential may need to be evaluated in certain scenarios outlined in the FDA's 2012 DDI draft guidance1.
  2. We have extensive experience (including publications2-3 and patents4-5) related to assessing the in vitro DDI potential of biologics. The following comments are focused on this experience.
  3. Plated human hepatocytes have been successfully utilized in the evaluation of small molecule drugs' DDI potential for many years. In contrast, the clinical relevance of the use of human hepatocytes in these evaluations, in which the cells are treated with a new molecular entity followed by measurements of cytochrome P450 or transporters expression or activity, is not well established for TPs. The ability of a TP to stimulate cytokine release and the established role of these molecules in suppressing expression of drug metabolizing enzymes and transporters constitute a challenge largely confined to biologics. The limitations of the current application of isolated hepatocytes for testing TP's DDI are related to (1) typically investigating a single recombinant cytokine at a time; (2) the absence of other relevant cell types present in the liver, blood and elsewhere in the body that may be a source of the cytokines, as well as, (3) failing to recapitulate relevant characteristics of a specific disease in vitro.
  4. Sekisui XenoTech's experience in evaluating the in vitro DDI perpetrator potential of biologics is based on a novel assay comprising treatment of whole human blood with drug to stimulate the release of cytokines from peripheral blood mononuclear cells (PBMCs). Plasma is separated from treated blood and then added to hepatocytes to evaluate CYP enzyme and/or transporter expression. All of the cytokines released into the plasma in response to the biologic are therefore evaluated followed by a comparison of the cytokine-mediated versus the direct effects of the drug on CYP or transporter expression. Direct effects of a TP may be observed in cultures treated with the TP itself rather than with the biologic-stimulated plasma. The principles of the method were established with the demonstration of cytokine-mediated but not direct effects of antiCD28 Mab on CYP mRNA expression and enzyme activity2.
  5. The advantages of this test system, as compared with the current application of isolated hepatocytes, are (1) testing of the plurality of the endogenous cytokines released by the PBMCs in response to a biologic as part of a molecular regulatory network, (2) allowing for an interaction of hepatocytes with PBMCs and, in the case of co-culture of hepatocytes and liver macrophages, Kupffer cells2, as well as, (3) the ability to recapitulate in vitro some of the relevant characteristics of a specific disease by substituting whole blood from target patients for the blood of healthy volunteers. Some limitations of this test system include the fact that cytokine release from cells other than those present in whole blood and co-culture, such as dendritic cells present at the site of drug injection are not accounted for. Additionally, the method doesn't account for the in vivo clearance of the cytokines. Nevertheless, this assay has proven utility with biologics, as exemplified by the recently published evaluation of DDI potential of an albumin-fused human growth hormone as compared with the unmodified recombinant protein3.
  6. Because published and proprietary client data generated according to our method are consistent with the expected interactions of the biologics with the immune system and their consequences for the regulation of CYP enzymes and transporters, we submit that the procedure has a significant potential to reduce the DDI risk associated with some TPs and other biologics.”
 
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