Serostim (Somatropin) - Description and Clinical Pharmacology

DESCRIPTION

Serostim^® is a human growth hormone (hGH) produced by recombinant DNA technology. Serostim^® has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. Serostim^® is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the hGH gene. Serostim^® is secreted directly through the cell membrane into the cell-culture medium for collection and purification.

Serostim^® is a sterile lyophilized powder intended for subcutaneous injection after reconstitution to its liquid form.

Vials of Serostim^® contain either 4 mg, 5 mg, or 6 mg. Each vial contains the following:

	Vials
	4 mg	5 mg	6 mg
Component
Somatropin	4 mg	5 mg	6 mg
Sucrose	27.3 mg	34.2 mg	41 mg
Phosphoric acid	0.9 mg	1.2 mg	1.4 mg

Each 4 mg multi-vial is supplied in a combination package with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution.

Each 5 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 6.5 to 8.5 after reconstitution.

Each 6 mg single-use vial is supplied in a combination package with Sterile Water for Injection, USP. The pH is adjusted with sodium hydroxide of phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution.

CLINICAL PHARMACOLOGY

Mechanism of Action

Serostim^® is an anabolic and anticatabolic agent which exerts its influence by interacting 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 by insulin-like growth factor-1 (IGF-1).

Pharmacodynamics

Effects on Protein, Lipid and Carbohydrate Metabolism

A one-week study in 6 patients with HIV-associated wasting has shown that treatment with Serostim^® 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism.

Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein Serostim^® vs. placebo were administered daily for 12 weeks to patients with HIV Lipodystrophy [see Clinical Studies].

Effects on Nitrogen and Mineral Retention

In the one-week study in 6 patients with HIV-associated wasting, treatment with Serostim^® resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during Serostim^® therapy was consistent with retention of these elements in lean tissue.

Physical Performance

Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials [see Clinical Studies]. In both studies, work output improved significantly in the group receiving Serostim^® 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with Serostim^® therapy.

Pharmacokinetics

Absorption: The absolute bioavailability after subcutaneous was determined to be 70 to 90%. The mean t½ after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (approximately 4.0 hrs. vs. 0.6 hrs.), indicating that the subcutaneous absorption of somatropin is a rate-limiting process.

Distribution: The steady-state volume of distribution (Mean ± SD) following intravenous administration of somatropin in normal male volunteers is 12.0 ± 1.08 L.

Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation.

Elimination: The t½ in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg somatropin subcutaneously was 4.28 ± 2.15 hrs, similar to that observed in normal male volunteers. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of daily dosing as indicated.

Specific Populations:

Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV.

Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV.

Race: No studies have been conducted to determine the effect of race on the pharmacokinetics of Serostim^®.

Renal Impairment: Subjects with chronic renal failure tend to have decreased somatropin clearance compared to those with normal renal function. However, no studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of Serostim^®.

Hepatic Impairment: No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetic of Serostim^®.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies for carcinogenicity have not been performed with Serostim^®. There is no evidence from animal studies to date of Serostim^®-induced mutagenicity or impairment of fertility.

CLINICAL STUDIES

HIV-Associated Wasting or Cachexia

The clinical efficacy of Serostim^® in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy. There was no increase in the incidence of Kaposi's sarcoma (KS), lymphoma, or in the progression of cutaneous Kaposi's sarcoma in clinical studies of Serostim. Patients with internal KS lesions were excluded from the studies. Potential effects on other malignancies are unknown.

Clinical Trial 1:

A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe HIV wasting taking nucleoside analogue therapy (pre-HAART era). The primary endpoint was body weight. Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing. Patients meeting the inclusion/exclusion criteria were treated with either placebo or Serostim^® 0.1 mg/kg daily. Ninety-six percent (96%) were male. The average baseline CD4 count/microliter was 85. The results from one hundred forty (140) evaluable patients were analyzed (those completing the 12-week course of treatment and who were at least 80% compliant with study drug). After 12 weeks of therapy, the mean difference in weight increase between the Serostim^®-treated group and the placebo-treated group was 1.6 kg (3.5 lb). Mean difference in lean body mass (LBM) change between the Serostim^®-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA. Mean increase in weight and LBM, and mean decrease in body fat, were significantly greater in the Serostim^®-treated group than in the placebo group (p=0.011, p<0.001, p<0.001, respectively) after 12 weeks of treatment (Figure 1). There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1).

Treatment with Serostim^® resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving Serostim^® (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM.

Figure 1: Mean Changes in Body Composition

Figure 2: Median Treadmill Work Output

Clinical Trial 2:

A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia. The primary efficacy endpoint was physical function as measured by cycle ergometry work output. Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers. Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of Serostim^®, or approximately 0.1 mg/kg daily at bedtime of Serostim^®. All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy. The average baseline CD4 count/µL was 446. Six hundred forty-six patients (646) completed the 12-week study and continued in the Serostim^® treatment extension phase of the trial.

Clinical Trial 2 results are summarized in Tables 4 and 5:

Table 4: Mean (Median) of Cycle Work Output (kJ) Response after 12 weeks of Treatment ITT Population

	Placebo	Half-Dose Serostim 1	Full-Dose Serostim 2
Cycle work output (kJ)	n=222	n=230	n=218
Baseline	25.92 (25.05)	27.79 (26.65)	27.57 (26.30)
Change from baseline	-0.05 (-0.25)	2.48 (2.30)	2.52 (2.40)
Percent change from baseline	0.2%	8.9%	9.1%
Difference from Placebo
Mean (2-sided 95% C.I.)	-	2.53 3 (0.81, 4.25)	2.57 (0.83, 4.31)
Median	-	2.55	2.65

The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the Serostim^® 0.1 mg/kg daily group (p<0.01) and by 2.53 kJ in the Serostim^® 0.1 mg/kg every other day group (p<0.01) compared with placebo (Table 4). Cycle work output improved approximately 9% in both active treatment arms and decreased <1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with Serostim^® and placebo (Table 5). The LBM results obtained by BIS were confirmed with DXA.

Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of Serostim^® in Clinical Trial 2.

Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued Serostim^® treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued Serostim^® treatment.