Pharmacokinetics and Metabolism
The earliest pharmacokinetic studies were conducted with pit-hGH. The pharmacokinetic profiles of pit-hGH, met-rhGH and rhGH have been compared (Hansen, 2002; Laursen, 2004) and shown to be very similar. The pharmacokinetics of hGH have been studied in normal, healthy children and adults, and a variety of patient populations (Jorgensen, 1991; Hansen, 2002; Laursen, 2004).
Exogenously administered pit-hGH, met-rhGH and rhGH are rapidly cleared following intravenous (IV) injection with terminal half-lives of approximately 15 to 20 minutes (Hansen, 2002; Laursen, 2004). Distribution volumes usually approximate the plasma volume. hGH clearance in normal subjects ranges from 2.2 to 3.0 mL/kg/min. hGH clearance decreases with increasing serum GH concentrations, most likely due to saturation of hGH receptors at concentrations >10 to 15 mg/L (Hansen, 2002). Comparative analyses of total hGH clearance have not shown consistent population differences based on age, sex or body composition. However, hGH clearance is controlled by a complex interaction between free hGH, GHBP-bound hGH and GH receptor status (Hansen, 2002). Individual subject variations in GHBP or GH receptor levels may result in substantial differences in hGH clearance.
hGH is slowly, but relatively completely, ab-sorbed after either IM or SC injection. Time to peak concentration ranges from 2 to 4 hours following IM bolus administration and 4 to 6 hours following SC bolus administration (Jorgensen, 1991; Laursen, 2004). SC administered rhGH is approximately 50% to 80% bioavailable (Laursen, 2004). The rate of absorption of hGH is slightly faster after injection in the abdomen compared with the thigh (Laursen, 2004), but the extent of absorption is comparable. Elimination half-lives following extravascular administration (2–5 hours) are usually longer than the IV terminal half-lives indicating absorption rate-limited kinetics.
hGH pharmacokinetics in the presence of growth hormone deficiency, diabetes, obesity, critical illness or diseases of the thyroid, liver and kidney have been evaluated. Results suggest disposition is not significantly altered compared with normal subjects except in severe liver or kidney dysfunction (Hansen, 2002; Haffner et al., 1994; Owens et al., 1973; Cameron et al., 1972). The reduction in clearance observed in severe liver (30%) or kidney dysfunction (40–75%) is consis-tent with the role of the liver and kidney as major organs of hGH elimination.
Both the kidney and the liver have been shown to be important in the clearance of hGH in humans(Hansen, 2002). The relative contribution of each organ has not been rigorously quantitated in humans, but the preponderance of studies in laboratory animals and in isolated perfused organ systems suggest a dominant role for the kidney at pharmaco-logic levels of hGH. Receptor-mediated uptake of hGH by the liver is the major extra-renal clearance mechanism (Harvey, 1995).