Recombinant Mammalian Cell-Derived Somatropin
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Recombinant mammalian cell-derived somatropin (hereafter referred to as somatropin) is human growth hormone produced by recombinant DNA technology. Somatropin, an established treatment for growth hormone-deficient children of short stature, has recently been shown to have beneficial effects in adult patients with HIV-associated wasting. This condition is characterised by the preferential loss of lean body mass (LBM) with relative conservation of body fat.
Somatropin produces protein anabolic and anticatabolic effects in patients with HIV-associated wasting. In HIV-infected male patients with this condition, increased nitrogen retention, decreased protein oxidation, increased lipid oxidation, increased bodyweight and increased resting energy expenditure were evident after treatment with subcutaneous somatropin 0.1 mg/kg/day for 7 days. Statistically significant increases in LBM, bodyweight (vs baseline and placebo) and work output (vs placebo) during treadmill exercise (a measure of physical function), and a significant decrease in body fat (vs baseline and placebo) occurred in similar patients who received somatropin for 12 weeks in a large double-blind randomised trial. These patients received concomitant antiretroviral therapy for the duration of the trial. Available data indicate that somatropin does not increase HIV replication in patients with HIV disease who are receiving concomitant antiretroviral medication.
The inconclusive results of quality-of-life assessments in patients with HIV-associated wasting receiving treatment with somatropin may have been related to the lack of a suitable instrument for measuring quality of life in this patient population. Further investigation is required to definitively establish the effects of the drug on this outcome measure.
Adverse events commonly observed with somatropin administered over ≤ 12 weeks include tissue swelling or puffiness, arthralgia or myalgia and diarrhoea. These events occurred in significantly more somatropin than placebo recipients in a large double-blind trial. Adverse events associated with somatropin are generally mild to moderate in severity and resolve after dosage reduction or discontinuation of somatropin treatment. The longer term tolerability profile of the agent in patients with HIV-associated wasting requires further clarification; however, unpublished data indicate that incidences of somatropin-related adverse events diminish over time.
In conclusion, somatropin appears to be a useful short term treatment for adult patients with HIV-associated wasting who continue to receive treatment with at least 2 antiretroviral drugs. Somatropin increases lean tissue, decreases body fat and improves physical function. Future pharmacoeconomic analyses may show that somatropin therapy has the potential to reduce direct healthcare costs, as a result of reduced time spent in hospital and less dependence on homecare support because of improved physical function. Although the ultimate positioning of somatropin has yet to be defined, recent data suggest that its role in the treatment of patients with HIV-associated wasting may be that of a short term intervention therapy, rather than a continuous treatment.
Overview of Wasting Associated with HIV Infection
Wasting is a common manifestation of HIV disease, affecting 19 to 25% of the HIV-infected population in the US. Bodyweight loss in affected patients occurs mainly as a preferential loss of lean body mass (LBM), which may be accompanied by a relative preservation of body fat.
The gradual decrease in body-cell mass and bodyweight that occurs in HIV-infected patients is associated with an increase in mortality. This association appears to be independent of other HIV-related factors. Altered metabolism, reduced energy intake, malabsorption and endocrine dysfunction contribute to the development of wasting in HIV-infected patients.
As the body composition of patients with HIV-associated wasting generally consists of a relatively low LBM content, strategies that increase protein anabolism and prevent protein catabolism (an anticatabolic effect) offer therapeutic potential. Various types of recombinant growth hormone, including mammalian cell-derived somatropin (hereafter referred to as somatropin), have shown protein anabolic and anticatabolic effects in normal and growth hormone-deficient humans and in patients in various catabolic states (such as after severe burns, or during critical illness). These findings led to the evaluation of somatropin in the treatment of patients with HIV-associated wasting.
Overview of Pharmacological Properties
Somatropin is identical in structure to endogenous human growth hormone and therefore shares the same pharmacological properties as the naturally occurring compound. It exerts direct effects by binding to specific receptors on various different types of cells, including hepatocytes, myocytes and lymphocytes. Indirect effects of the drug are mediated via the peptide hormone insulin-like growth factors (IGFs), particularly IGF-I.
During treatment with somatropin, protein anabolism and anticatabolism, resulting in an increase in lean body tissue, occur in patients with HIV-associated wasting. These metabolic effects (a significant increase in nitrogen retention and a significant decrease in protein oxidation) were observed in 6 male patients with HIV-associated wasting who received subcutaneous somatropin 0.1 mg/kg/day for 7 days. A significant mean increase in lipid oxidation (vs baseline) was also observed in these patients, who gained 2.0kg in bodyweight (which comprised lean tissue plus associated body water). In addition, a significant increase in resting energy expenditure was recorded. Plasma IGF-I levels increased significantly from baseline in both study groups. In a subsequent double-blind trial in which patients with HIV-associated wasting received either somatropin 0.1 mg/kg/day (n = 90) or placebo (n = 88) for 12 weeks, IGF-I levels also increased significantly from baseline in the somatropin-treated patients. At week 12, there was a significant correlation between increases in IGF-I levels and LBM. As observed in the earlier metabolic study, a significant increase in total body water volume occurred during treatment with somatropin. This increase was similar to that expected to occur as a result of hydration of lean body tissue.
Somatropin (derived from Escherichia coli) has been shown to enhance HIV-1 proliferation (to a variable extent) in vitro in peripheral blood mononuclear cells. However, HIV production was not increased when either zidovudine, didanosine or lamivudine was added to a somatropin-containing HIV culture. Thus, concomitant antiretroviral drug therapy is strongly recommended for patients with HIV-associated wasting receiving treatment with the drug. In patients who received somatropin with concomitant antiretroviral drug therapy in a large double-blind trial, assessments of viral burden showed that the drug did not enhance HIV replication.
Evidence that somatropin stimulates haemopoiesis (statistically significant increases in total white blood cell and absolute neutrophil counts versus placebo) in patients with HIV-associated wasting has been reported in recent placebo-controlled trials that included a total of 355 patients. Whether or not somatropin ameliorates the myelosuppressive activity of zidovudine in HIV-infected patients with wasting remains to be confirmed.
Data on the pharmacokinetic properties of somatropin in patients with HIV-associated wasting are relatively limited, with most published information relating to the pharmacokinetics of the drug (formulation different from that currently marketed) in adult male and female volunteers.
The absolute bioavailability of somatropin was between 70 and 90% in healthy volunteers after single subcutaneous or intramuscular doses of 1.3 mg/m2 to 20mg. In healthy volunteers (in whom endogenous growth hormone production had been down-regulated), the absolute bioavailability of somatropin was higher after a single subcutaneous 8IU dose (93%) than after the same dose administered intramuscularly (84%).
A higher mean maximum serum somatropin concentration (Cmax) was reached after a single intramuscular 1.3 mg/m2 dose of the drug than after subcutaneous administration of the same dose. However, serum somatropin concentrations were sustained for longer after subcutaneous than after intramuscular injection. The mean time to reach Cmax (tmax) was 5 to 6 hours after single subcutaneous doses of 1.3 mg/m2 in male volunteers, whereas tmax after a single intramuscular dose of 1.3 mg/m2 was 3.8 hours.
The mean somatropin area under the serum concentration-time curve value was lower and the mean tmax longer in patients with HIV-associated wasting receiving multiple subcutaneous doses of somatropin (6 mg/day) than in adult volunteers after receiving the same dosage.
Somatropin is degraded by proteolysis in various parts of the body, including the kidneys. Total metabolic clearance of the drug is 15 L/h; a negligible amount of the drug is excreted renally. In patients with HIV infection-associated wasting, the mean serum elimination half-life of subcutaneously administered somatropin (6 mg/day) is about 4.3 hours.
The therapeutic efficacy of somatropin has been evaluated in trials conducted in adult patients (mostly males) with HIV-associated wasting. These trials were of relatively short duration (≤12 weeks). Few published data are yet available regarding the longer term efficacy of the agent in HIV-infected patients with this condition. However, preliminary unpublished information suggests that efficacy gains are maintained for at least 6 months. Sustained beneficial responses occurred in 6 patients for 3 months after discontinuation of somatropin treatment.
In a double-blind, placebo-controlled clinical trial, somatropin 0.1 mg/kg/day, administered for 12 weeks, significantly increased LBM (vs baseline and placebo), bodyweight (vs baseline and placebo) and work output during treadmill exercise (a measure of physical function) [vs placebo] and decreased body fat (vs baseline and placebo) in patients with HIV-associated wasting. At week 12, work output (assessed by treadmill exercise measurements) had increased by 13.2 and 2.5% in the somatropin and placebo recipients, respectively.
Assessments of quality of life in patients receiving somatropin were made using several instruments validated for assessing quality of life in patients with HIV disease receiving chronic antiretroviral therapy. Quality-of-life scores at week 12 did not differ significantly between recipients of somatropin or placebo in the first double-blind trial conducted in patients with HIV-associated wasting. In contrast, initial results of a later trial indicated that significant improvements in overall quality of life and in appearance were experienced by patients treated with somatropin.
Most information on the tolerability of somatropin in patients with HIV-associated wasting has been obtained from short term (≤12 week) trials. Somatropin appears to be well tolerated in adult patients with HIV-associated wasting receiving the drug for ≤12 weeks. The most common reported adverse events include tissue swelling or puffiness, myalgia or arthralgia, diarrhoea and nausea. These events are generally mild to moderate in severity and resolve over time or after either dosage reduction or treatment discontinuation. Tissue swelling or puffiness, myalgia or arthralgia and diarrhoea occurred in significantly more somatropin than placebo recipients in a large double-blind trial. No increases in the incidences of Kaposi’s sarcoma, the progression of cutaneous Kaposi’s sarcoma or the incidence of lymphoma were observed in patients with HIV-associated wasting who received somatropin in clinical trials.
The longer term (> 12 weeks) tolerability of somatropin has yet to be clarified. However, unpublished data indicate that the incidence of adverse events decreases over time.
Dosage and Administration
For adult patients with HIV-associated wasting who weigh <35kg, the recommended dosage of somatropin is 0.1 mg/kg/day, administered subcutaneously at bedtime. Dosages of 4, 5 and 6 mg/day are recommended for the treatment of patients weighing 35 to 45kg, 45 to 55kg and >55kg, respectively. Rotation of the site of injection is advised. It is strongly recommended that patients receiving somatropin treatment should receive concomitant combination antiretroviral drug therapy.
Although information is relatively limited on the use of somatropin in children with HIV infection-associated growth retardation (which may be the paediatric analogue of wasting), initial results of clinical trials indicate that a dosage of 40 µg/kg/day for 6 to 9 months is well tolerated by this patient population.
KeywordsGrowth Hormone Adis International Limited Lean Body Mass Work Output Recombinant Human Growth Hormone
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