Drug Interaction Assessment Strategies: Small Molecules versus Therapeutic Proteins

Abstract

This chapter is not intended to give an expansive and detailed review of all ofthe methods and assays used for drug‐drug interaction (DDI) assessment during small molecule drug (SMD) development because this has already been accomplished by others in the field. Rather, general concepts and methods will be discussed for some of the typical assays undertaken in SMD development, including whether these methods can be, should be, or already have been applied in the context of therapeutic protein (TP)‐DI assessments. This chapter serves as a starting point for understanding the complexity and difficulties in assessing TP‐DIs.

Critical Review of Preclinical Approaches to Investigate Cytochrome P450–Mediated Therapeutic Protein Drug-Drug Interactions and Recommendations for Best Practices: A White Paper

“…Unlike SMD metabolism and DDI, for which multiple in vitro methods are used routinely, there are only a few in vitro models that have been used for predictive assessment of TP-DDIs (AbdelRazzak et al, 1993;Aitken and Morgan, 2007;Dickmann et al, 2011;Dallas et al, 2013b). Primary human hepatocytes are the current in vitro model of choice for studies on the effects of individual proinflammatory cytokines on hepatic cytochrome P450 expression and activity.…”

“…Several recent workshops have addressed TP-DDIs, including the 2010 American Association of Pharmaceutical Scientists workshop on "Strategies to Address Therapeutic ProteinDrug Interactions during Clinical Development" (Girish et al, 2011), and related roundtables at the National Biotechnology Conference in 2012 . Recent publications from academia, industry, and regulatory agencies have summarized the mechanisms involving TP-DDIs, evaluations of TP-DDIs included in Biologics License Application (BLA) submissions, and current strategies for the evaluation of TP-DDI potential during drug development (Morgan, 2009;Huang et al, 2010;Lee et al, 2010;Girish et al, 2011;Kraynov et al, 2011;Zhou and Mascelli, 2011;Lloyd et al, 2012;Dallas et al, 2013b;Slatter et al, 2013). As a result of discussions at several of these meetings, a collaboration among academia, industry, and regulatory agencies was initiated under the leadership of the TP-DDI Steering Committee (see Appendix) to address knowledge gaps in the mechanisms of TP-DDI, the relevance of in vitro systems, current industry practices for assessing these interactions, and to develop a general framework of risk-based approaches for TP-DDI assessment during drug development.…”