Saizen Mechanism of Action

Pharmaco-therapeutic group: Anterior pituitary lobe hormones and analogues. ATC code: HO1A.
Pharmacology: Pharmacodynamics: Saizen contains recombinant human growth hormone produced by genetically engineered mammalian cells.
It is a peptide of 191 amino acids identical to human pituitary growth hormone with respect to aminoacid sequence and composition as well as peptide map, isoelectric point, molecular weight, isomeric structure and bioactivity.
Growth hormone is synthesised in a transformed murine cell line that has been modified by the addition of the gene for pituitary growth hormone.
Saizen is an anabolic and anticatabolic agent which exerts effects not only on growth but also on body composition and metabolism. It interacts with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes and hematopoietic cells. Some, but not all of its effects are mediated through another class of hormones known as somatomedins (IGF-1 and IGF-2).
Depending on the dose, the administration of Saizen elicits a rise in IGF-1, IGFBP-3, non-esterified fatty acids and glycerol, a decrease in blood urea, and decreases in urinary nitrogen, sodium and potassium excretion. The duration of the increase in GH levels may play a role in determining the magnitude of the effects. A relative saturation of the effects of Saizen at high doses is probable. This is not the case for glycemia and urinary C-peptide excretion, which are significantly elevated only after high doses (20 mg).
In a randomised clinical trial, three years treatment of prepubertal short children born SGA with a dose of 0.067 mg/kg/day resulted in a mean gain of +1.8 height-SDS. In those children who did not receive treatment beyond 3 years, part of the treatment benefit was lost, but the patients retained a significant gain of +0.7 height-SDS at final height (p<0.01 compared to baseline). Patients who received a second treatment course after a variable period of observation experienced a total gain of +1.3 height-SDS (p=0.001 compared to baseline) at final height. (The mean cumulative treatment duration in the latter group was 6.1 years). The gain in height-SDS (+1.3 ± 1.1) at final height in this group was significantly (p<0.05) different from the gain in height-SDS obtained in the first group (+0.7 ± 0.8) that received only 3.0 years of treatment on average.
A second clinical trial investigated two different dose regimens over four years. One group was treated with 0.067 mg/kg/day for 2 years and then observed without treatment for 2 years. The second group received 0.067mg/kg/day in the first and third year and no treatment in the second and fourth year. Either treatment regimen resulted in a cumulative administered dose of 0.033/mg/kg/day over the four-year study period. Both groups showed a comparable acceleration of growth and a significant improvement of +1.55 (p<0.0001) and +1.43 (p<0.0001) height-SDS respectively at the end of the four year study period. Long-term safety data are still limited.
Chronic Renal Failure: In an open label study, children with chronic renal failure (17 post-transplant, 27 on dialysis and 37 compensated CRF) and growth failure, received a weekly dose of 0.35 mg/kg per week (28 IU/m²/week) Saizen. Chronic renal failure was defined as patients with end-stage renal disease on dialysis, or 12 months post kidney transplant, or compensated renal insufficiency with glomerular filtration rate (GFR) <30 mL/min per 1.73 m². Growth failure was defined as height of at least 2 standard deviation (SD) and growth velocity of at least 0.5 SD below the mean for chronological age (CA). Each patient's pre-treatment growth period served as a control for subsequent treatment periods. The mean (±SD) CA was 8.6 ± 3.9 years with a bone age (BA) of 5.7 ± 3.0 years. For the group, height velocity (HV) increased by +4.4 ± 4.0 cm/yr (n=63, p<0.001) at 12 months and by +3.0 ± 3.6 cm/yr (n=44, p<0.001) at 2 years compared to baseline. Similarly, Height SDS increased by +0.7 ± 0.7 (n=63, p<0.001) at 12 months and by +1.2 ± 1.2 (n=44, p<0.001) at 2 years. The potential effect on final height was assessed by measuring the change in height age (HA) relative to the change in BA. The ΔHA/ΔBA ratio was equal to or greater than 1 at both one and 2 years of treatment indicating preservation of final height potential.
Idiopathic Short Stature: In a randomized, open-label, two-arm parallel, treatment vs delayed treatment group study, 90 children with ISS received 0.067 mg/kg/day of Saizen 6 days per week, weight-based dose, for 12 months (12 months of treatment group), or 6 months of no treatment followed by 6 months of treatment (control group). Patients were enrolled based on height below third percentile according to national growth charts, stimulated growth hormone secretion >10 μg/L, and prepubertal status. The mean (±SD) CA was 6.8 ± 1.6 years with a BA of 5.2 ± 1.6 years. At six months, the mean change from baseline in HV, Height and Height SDS was significantly greater in the 59 children in the treated group (HV: +4.45 ± 2.70 cm/year, Height: +5.41 ± 1.04 cm, Height SDS: +0.59 ± 0.21, respectively) compared to the 29 un-treated children in the control group (HV: 1.01 ± 3.15 cm/year, Height: 3.10 ± 0.84 cm, Height SDS: +0.08 ± 0.19 respectively; p<0.0001). After 12 months of treatment, the 12-month treatment group continued to see improvement over baseline in all parameters evaluated (HV: +3.77 ± 2.21 cm/year, Height: +9.78 ± 1.35 cm, and Height SDS: +0.96 ± 0.27). The control group showed increase from baseline in all parameters after 6 months of treatment, similar to the increases observed at the 6 month time point of the treated group (HV: +2.86 ± 1.95 cm/year, Height: +8.24 ± 1.47 cm, and Height SDS: +0.62 ± 0.27).
Pharmacokinetics: The pharmacokinetics of Saizen are linear at least up to doses of 8 IU (2.67 mg). At higher doses (60 IU/20 mg) some degree of non-linearity cannot be ruled out, however with no clinical relevance.
Following IV administration in healthy volunteers the volume of distribution at steady-state is around 7 L, total metabolic clearance is around 15 L/h while the renal clearance is negligible, and the drug exhibits an elimination half-life of 20 to 35 min.
Following single-dose SC and IM administration of Saizen, the apparent terminal half-life is much longer, around 2 to 4 hours. This is due to a rate limiting absorption process.
Maximum serum growth hormone (GH) concentrations are reached after approximately 4 hours and serum GH levels return to baseline within 24 hours, indicating that no accumulation of GH will occur during repeated administrations.
The absolute bioavailability of both routes is 70-90%.
Saizen solutions for injection (5.83 and 8.00 mg/ml) administered subcutaneously have been shown to be bioequivalent versus the 8 mg freeze-dried formulation.
Toxicology: Preclinical safety data: The local tolerability of Saizen solution for injection was shown to be good and suitable for SC administration, when injected in animals at a concentration of 8.00 mg/ml and volumes of 1 ml/site.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Reproductive toxicology studies do not indicate any adverse effect on fertility and reproduction, despite administration of doses sufficiently high to produce some pharmacological effects on growth.