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.
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