Utility ofIn VitroMethods in Drug–Drug Interaction Assessment and Prediction for Therapeutic Biologics

Abstract

Due to the long half‐life of commonly used therapeutic proteins (TPs) such as mAbs and the difficulty in many cases to recruit patients for trial enrollment, the conduct of well‐designed clinical interaction studies is generally costly and difficult. Therefore, there is astrong desire to develop in vitro approaches allowing predictions of whether significantinteractions between TPs and small molecules are likely. This chapter providesan overview of the current literature on the effects of proinflammatory cytokines on absorption, distribution, metabolism, and excretion (ADME) genes in vitro and provides a perspective on the current challenges and future opportunities to establish improved in vitro systems.

Establishment of a Hepatocyte-Kupffer Cell Coculture Model for Assessment of Proinflammatory Cytokine Effects on Metabolizing Enzymes and Drug Transporters

“…The extent of CYP3A4 activity downregulation observed in Hep: KC cultures by IL-6 (61%-97%) was comparable to those reported in numerous studies using human hepatocyte monocultures (20%-80%) (Dickmann et al, 2011;Dallas et al, 2012;Nguyen et al, 2013). This finding indicates that the coculture model is responding as expected to proinflammatory cytokine stimulation.…”

“…In general, the focus for TP-DDIs has been on cytokines [e.g., IL-1, IL-6, and tumor necrosis factor-a (TNF-a)] and cytokine modulators, as these are known to alter the expression levels of various drug-metabolizing enzymes and transporters in hepatocyte in vitro systems (Aitken et al, 2006;Fardel and Le Vée, 2009;Nguyen et al, 2013). Cytokines have differential effects on cytochrome enzymes, suggesting the involvement of diverse mechanisms in P450 downregulation (Gu et al, 2006;Urquhart et al, 2007;Lee et al, 2009;Harvey and Morgan, 2014).…”

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

“…Overall, high interlaboratory variability in cytochrome P450 suppression by cytokines has been noted (Abdel-Razzak et al, 1993;Donato et al, 1997;Pascussi et al, 2000;Aitken and Morgan, 2007;Nguyen et al, 2013). Many factors could contribute to variability, including experimental design (e.g., plate format, seeding densities, and time points), intrinsic donor attributes (age, disease state, and medical history), and sources of reagents (cytokines and culture media) Nguyen et al, 2013).…”

“…Abdel-Razzak et al (1993) and Donato et al (1993) showed that proinflammatory cytokines such as IL-6, tumor necrosis factor-a (TNF-a), and IFN-g suppressed the constitutive expression of cytochrome P450 enzymes in human hepatocyte culture. The magnitude and direction of effects on cytochrome P450 activity and expression depended on the particular cytokine and cytochrome P450 isoenzyme measured (Nguyen et al, 2013). To maximize in vitro response, cytokine concentrations were based on or exceeded the maximum levels observed during the acute phase of inflammation (Muntane-Relat et al, 1995;Chen et al, 2011).…”

Therapeutic Protein Drug Interactions: A White Paper From the International Consortium for Innovation and Quality in Pharmaceutical Development

“…In vitro investigations of cytokine modulation have previously involved spiking single cytokines into hepatocytes and such models may not consider the complex interplay of cytokines and transcription factors that occur in an inflammatory disease state. For instance, IL‐2 receptors are not found in human hepatocytes, and so it has been postulated based on in vitro data in hepatocyte‐Kupffer cell cocultures that IL‐2 antagonists could not therefore alter CYP activity directly 56 . However, this does not explain the decrease in hepatic mRNA observed when high doses of IL‐2 were infused in cancer patients and total CYP expression decreased by 34% 41 …”