Effects of Albumin-Fused Human Growth Hormone TV-1106 on CYP Enzyme Expression in Human Hepatocytes
Drug-drug interactions involving therapeutic proteins that can modulate effects of cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to regulatory agencies and pharmaceutical industry sponsors in recent years. The well-documented therapeutic protein DDI mechanism involves pro-inflammatory, cytokine-mediated changes in drug-metabolizing enzymes. Multiple in vitro and a number of in vivoHuman studies have demonstrated the effect of individual cytokines and their modulators on P450s and transporters (Evers et al., 2013).
TV-1106 is recombinant Human albumin (rhA), genetically fused at its C-terminus to recombinant Human growth hormone (rhGH) to prolong systemic circulation of rhGH and improve its therapeutic activity (Osborn et al., 2002; Sleep, 2014). Phase 1 clinical trial of TV-1106 demonstrated that the drug is well tolerated, has a prolonged half-life in the circulation, and is biologically active in adults with GH deficiency.
GH also enhanced pro-inflammatory cytokines IL1-alpha, IL-6 and TNF-alpha production by lipopolysaccharide (LPS)-activated monocytes in whole blood and its administration at high doses to critically ill adults was associated with an increase in morbidity and mortality (Uronen-Hansson et al., 2003). GH has been shown to be a major determinant of hepatic CYP expression in rats (Morgan et al., 1998). An in vitro study showed an increased CYP3A4 gene expression in cultured Human hepatocytes after exposure to GH (Liddle et al., 1998). In healthy elderly men GH induces CYP1A2 and, to a lesser extent, inhibits CYP2C19, but it exerts no effects on CYP2D6 and CYP3A4 enzymes (Jurgens et al., 2002).
An evaluation of TV-1106 effects on plasma cytokines and subsequently on hepatic drug metabolism is warranted by the fact that rhGH is known to modulate plasma cytokines in GH-deficient and normal children of short stature (Bozzola et al., 2003; Pagani et al., 2005).
An in vitro test system to examine direct- and cytokine-mediated effects of therapeutic proteins on hepatic drug metabolism that is based on treatment of whole blood with the drug, followed by separation of plasma and application of that plasma to cultured hepatocytes, has been recently developed (Czerwinski et al., 2015). Here we evaluated the ability of TV-1106 to stimulate cytokine release in whole blood and the effect of up to 50% plasma from TV-1106-treated blood on CYP expression in cultured Human hepatocytes and compared the direct effects of treating primary cultures of Human hepatocytes with TV-1106 and rhGH on the expression of CYP enzymes.