Humatrope (Somatropin) - Description and Clinical Pharmacology

DESCRIPTION

Humatrope^® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.

Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution. Humatrope is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.

VIAL — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5–mL vial of diluting solution. The diluent contains Water for Injection with 0.3% Metacresol as a preservative and 1.7% glycerin.

CARTRIDGE — The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. The 6, 12, and 24 mg cartridges contain respectively: mannitol 18, 36, and 72 mg; glycine 6, 12, and 24 mg; dibasic sodium phosphate 1.36, 2.72, and 5.43 mg. Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting solution. The diluent contains Water for Injection; 0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg cartridges, respectively.

CLINICAL PHARMACOLOGY

General

Linear Growth  — Humatrope stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth hormone–deficient pediatric patients and patients with Turner syndrome with Humatrope produces increased growth rate and IGF–I (Insulin–like Growth Factor–I/Somatomedin–C) concentrations similar to those seen after therapy with human growth hormone of pituitary origin.

In addition, the following actions have been demonstrated for Humatrope and/or human growth hormone of pituitary origin.

A. Tissue Growth  — 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatrope or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF–I, which may play a role in skeletal growth, are low in the serum of growth hormone–deficient pediatric patients but increase during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in short–statured pediatric patients who lack endogenous growth hormone as compared with normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells.

B. Protein Metabolism  — Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.

C. Carbohydrate Metabolism  — Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have an increased incidence of glucose intolerance. Administration of human growth hormone to normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and postprandial insulin levels although mean values remained in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A_1c levels remained in the normal range.

D. Lipid Metabolism  — In growth hormone–deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

E. Mineral Metabolism  — Retention of sodium, potassium, and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatrope or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatrope.

Pharmacokinetics

Absorption  — Humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular administration, respectively.

Distribution  — The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg.

Metabolism  — Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products of growth hormone is returned to the systemic circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half–life of intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half–lives of 3.8 and 4.9 hours, respectively. The longer half–life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.

Excretion  — Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy.

Special Populations

Geriatric  — The pharmacokinetics of Humatrope has not been studied in patients greater than 65 years of age.

Pediatric  — The pharmacokinetics of Humatrope in pediatric patients is similar to adults.

Gender  — No studies have been performed with Humatrope. The available literature indicates that the pharmacokinetics of growth hormone is similar in both men and women.

Race  — No data are available.

Renal, Hepatic insufficiency  — No studies have been performed with Humatrope.

Table 1 Summary of Somatropin Parameters in the Normal Population ¹

	Cmax (ng/mL)	t1/2 (hr)	AUC0-∞ (ng•hr/mL)	Cls (L/kg•hr)	Vβ (L/kg)
0.02 mg (0.05 IU 2)/kg
iv
MEAN	415	0.363	156	0.135	0.0703
SD	75	0.053	33	0.029	0.0173
0.1 mg (0.27 IU)/kg
im
MEAN	53.2	4.93	495	0.215	1.55
SD	25.9	2.66	106	0.047	0.91
0.1 mg (0.27 IU)/kg
sc
MEAN	63.3	3.81	585	0.179	0.957
SD	18.2	1.40	90	0.028	0.301

Figure 1

CLINICAL TRIALS

Effects of Humatrope Treatment in Adults with Growth Hormone Deficiency

Two multicenter trials in adult–onset growth hormone deficiency (n=98) and two studies in childhood–onset growth hormone deficiency (n=67) were designed to assess the effects of replacement therapy with Humatrope. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The Nottingham Health Profile is a general health–related quality of life questionnaire. These four studies each included a 6–month randomized, blinded, placebo–controlled phase followed by 12 months of open–label therapy for all patients. The Humatrope dosages for all studies were identical: 1 month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day. Adult–onset patients and childhood–onset patients differed by diagnosis (organic vs. idiopathic pituitary disease), body size (normal vs. small for mean height and weight), and age (mean=44 vs. 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central laboratory.

Humatrope–treated adult–onset patients, as compared to placebo, experienced an increase in lean body mass (2.59 vs. –0.22 kg, p<0.001) and a decrease in body fat (–3.27 vs. 0.56 kg, p<0.001). Similar changes were seen in childhood–onset growth hormone–deficient patients. These significant changes in lean body mass persisted throughout the 18–month period as compared to baseline for both groups, and for fat mass in the childhood–onset group. Total cholesterol decreased short–term (first 3 months) although the changes did not persist. However, the low HDL cholesterol levels observed at baseline (mean=30.1 mg/mL and 33.9 mg/mL in adult–onset and childhood–onset patients) normalized by the end of 18 months of therapy (a change of 13.7 and 11.1 mg/dL for the adult–onset and childhood–onset groups, p<0.001). Adult–onset patients reported significant improvements as compared to placebo in the following two of six possible health–related domains: physical mobility and social isolation (Table 2). Patients with childhood–onset disease failed to demonstrate improvements in Nottingham Health Profile outcomes.

Two additional studies on the effect of Humatrope on exercise capacity were also conducted. Improved physical function was documented by increased exercise capacity (VO₂ max, p<0.005) and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552–557).

Two studies evaluating the effect of Humatrope on bone mineralization were subsequently conducted. In a 2–year, randomized, double–blind, placebo–controlled trial, 67 patients with previously untreated adult–onset growth hormone (GH) deficiency received placebo or Humatrope treatment titrated to maintain serum IGF–I within the age–adjusted normal range. In men, but not women, lumbar spine bone mineral density (BMD) increased with Humatrope treatment compared to placebo with a treatment difference of approximately 4% (p=0.001). There was no significant change in hip BMD with Humatrope treatment in men or women, when compared to placebo. In a 2–year, open–label, randomized trial, 149 patients with childhood–onset GH deficiency, who had completed pediatric GH therapy, had attained final height (height velocity <1 cm/yr) and were confirmed to be GH–deficient as young adults (commonly referred to as transition patients), received Humatrope 12.5 µg/kg/day, Humatrope 25 µg/kg/day, or were followed with no therapy. Patients who were randomized to treatment with Humatrope at 12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control in total body bone mineral content (BMC) (8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients treated with Humatrope at 25 µg/kg/day had no significant change in BMC. These results include data from patients who received less than 2 years of treatment. A greater treatment effect was observed for patients who completed 2 years of treatment. Increases in lumbar spine BMD and BMC were also statistically significant compared to control with the 12.5 µg/kg/day dose but not the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to control with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses lower than 12.5 µg/kg/day was not studied. The effect of Humatrope on the occurrence of osteoporotic fractures has not been studied.

Table 2 Changes ¹ in Nottingham Health Profile Scores ² in Adult–Onset Growth Hormone–Deficient Patients

Outcome Measure	Placebo (6 Months)	Humatrope Therapy (6 Months)	Significance 3
Energy level	-11.4	-15.5	NS
Physical mobility	-3.1	-10.5	p<0.01
Social isolation	0.5	-4.7	p<0.01
Emotional reactions	-4.5	-5.4	NS
Sleep	-6.4	-3.7	NS
Pain	-2.8	-2.9	NS