Biologic Services


In recent years, pharmaceutical drug development has increasingly shifted from small molecule based drugs to large molecule therapeutics also known as biologic drugs. This broad category of drugs includes monoclonal antibodies, hormones, growth factors, enzymes, vaccines, oligonucleotides and other large molecule therapeutics. While the evaluation of drug-drug interactions (DDIs) with small molecule drugs is well established, it is an area of growing concern and investigation for biologic drugs. Some biologic drugs have been shown to cause an inflammatory response, leading to elevated cytokine levels and subsequent suppression of drug metabolizing enzymes such as Cytochrome P450s (CYPs). The FDA recognizes in their 2012 Guidance for Industry on drug interactions that biologics should be evaluated in vitro or in vivo for their ability to alter the disposition of small molecule drugs (biologic-small molecule drug-drug interactions), particularly if the biologic is a cytokine or cytokine modulator.

In response to the FDA Guidance, Sekisui XenoTech has developed a novel* in vitro method to evaluate biologic-small molecule DDIs. This simple yet elegant method involves both the direct treatment of hepatocytes with a biologic drug; and the ex vivo treatment of whole human blood with a test biologic, the isolation of plasma and subsequent in vitro treatment of human hepatocytes with the plasma. Through this method, the immune response seen in blood is allowed to exert its effects on hepatocytes, providing for the complete assessment of a biologic's potential to regulate hepatic drug metabolizing enzymes.

Additionally, Sekisui XenoTech has evaluated biologics for clients with standard assays such as CYP inhibition in hepatocytes or microsomes, as well as CYP induction studies in human hepatocyte and Kupffer cell co-cultures. Kupffer cells comprise approximately 4-8% of total liver cell content and approximately 20% of non-parenchymal cells (Racanelli and Rehermann, 2006). Sekisui XenoTech's fresh plated hepatocyte and Kupffer cell co-cultures contain 0.6% to 24.1% Kupffer cells with a median value of 2.6% and average of 4.7%. The cytokine response of isolated Kupffer cells to stimulation with bacterial endotoxin (LPS) in vitro has been characterized by Sekisui XenoTech scientists (Lambert et al., 2013). Our in depth experience with biologic drugs allows us to design studies that would best fit your particular needs.

Sekisui XenoTech offers the following services for evaluation of biologics:

  • Our novel in vitro method for evaluation of biologic-small molecule DDI potential, includes:
      - Assessment of direct and Kupffer cell-mediated DDI potential; evaluated in   hepatocyte and Kupffer cell co-cultures
      - Assessment of immune-mediated DDI potential; evaluated in whole
        blood ex vivo and in hepatocyte and Kupffer cell co-cultures in vitro
  • Evaluation of CYP inhibition; evaluated in hepatocytes or human liver microsomes
  • Evaluation of CYP inhibition; evaluated in hepatocytes and Kupffer cell co-cultures

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ISSX 2013,"Endotoxin up-regulates the proinflammatory cytokines TNF-α and IL-6 in freshly-isolated human kupffer cells"

ISSX 2011, "An in vitro test system to evaluate drug-drug interactions with biologics"

ISSX 2011, "Temporal changes in CYP3A4 mRNA and activity following treatment of cultured human hepatocytes with interleukin-6 (IL-6): Implications for study design and endpoint selection"

ISSX 2009, "Inhibition of cytochrome P450 (CYP) enzymes, CYP1A2 and CYP2C8, by oligonucleotides in human liver microsomes (HLM): A system-dependent outcome"

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