A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Serostim Pharmacology, Pharmacokinetics, Studies, Metabolism - Somatropin (rDNA origin)
Serostim Pharmacology, Pharmacokinetics, Studies, Metabolism - Somatropin (rDNA origin)
CLINICAL PHARMACOLOGY
Serostim® [somatropin (rDNA origin) for injection]
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 another class of hormones known as somatomedins (IGF-1
and IGF-2).
AIDS-associated wasting is a metabolic disorder characterized
by abnormalities of intermediary metabolism resulting in weight loss, inappropriate
depletion of lean body mass (LBM), and paradoxical preservation of body fat.
LBM includes primarily skeletal muscle, organ tissue, blood and blood constituents,
and both intracellular and extracellular water. Depletion of LBM results in
muscle weakness, organ failure, and death. Unlike nutritional intervention for
AIDS-associated wasting, in which supplemental calories are converted predominantly
to body fat, Serostim® treatment resulted in an increase in LBM
and a decrease in body fat with a significant increase in body weight due to
the dominant effect of LBM gain.
Effects on Protein, Lipid, and Carbohydrate Metabolism:
A one-week study in 6 patients with HIV associated wasting
has shown that treatment with Serostim® improves nitrogen balance,
increases protein-sparing lipid oxidation, and has little effect on overall
carbohydrate metabolism.
Lean Body Mass Accrual:
In the same study, 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. In clinical
studies (12 weeks), Serostim® significantly increased lean body
mass. There was also a proportionate increase in intracellular and extracellular
fluid during Serostim® therapy suggesting accretion of normally
hydrated lean body tissue.
Physical Performance:
Treadmill performance was examined in a 12-week placebo-controlled
study. Work output improved significantly in the Serostim®-treated
group after 12 weeks of therapy and was correlated with LBM. No such correlation
was seen with body fat. 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 r-hGH therapy.
PHARMACOKINETICS
Subcutaneous Absorption: The absolute bioavailability
of Serostim® [somatropin (rDNA origin) for injection] after subcutaneous
administration of a formulation not equivalent to the marketed formulation was
determined to be 70-90%. The t½ (Mean ± SD) after subcutaneous administration
is significantly longer than that seen after intravenous administration to normal
male volunteers, down-regulated with somatostatin (3.94 ± 3.44 hrs. vs. 0.58
± 0.08 hrs.), indicating that the subcutaneous absorption of the clinically
tested formulation of the compound is slow and rate-limiting.
Distribution: The steady-state volume of distribution
(Mean ± SD) following IV administration of Serostim® in healthy
volunteers is 12.0 ± 1.08 L.
Metabolism: Although the liver plays a role in the metabolism
of growth hormone, 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 (Mean ± SD) in nine patients with
AIDS related wasting with an average weight of 56.7 ± 6.8 kg, given a fixed
dose of 6.0 mg r-hGH subcutaneously was 4.28 ± 2.15 hrs. The renal clearance
of r-hGH after subcutaneous administration in nine patients with AIDS related
wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears
to occur after 6 weeks of dosing as indicated.
Special Populations:
Pediatric: Available evidence suggests that r-hGH clearances
are similar in adults and children, but no clinical studies were conducted in
children with acquired immune deficiency syndrome or AIDS-related complex.
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 on Serostim® in normal volunteers or patients
infected with HIV.
Race: No data are available.
Renal Insufficiency: It has been reported that individuals
with chronic renal failure tend to have decreased hGH clearance compared to
normals, but there are no data on Serostim® use in the presence
of renal insufficiency.
Hepatic Insufficiency: A reduction in r-hGH clearance
has been noted in patients with severe liver dysfunction. However, the clinical
significance of this in HIV+ patients is unknown.
CLINICAL STUDIES
The clinical efficacy of Serostim® [somatropin
(rDNA origin) for injection] was assessed in two placebo-controlled clinical
trials. Of the 205 AIDS subjects exposed to GH, only 5 were women. All study
subjects received concomitant anti-HIV therapy.
Clinical Trial 1: A multicenter, double-blind, placebo-controlled
study compared Serostim® at an average daily dose of 0.1 mg/kg/day
administered subcutaneously to placebo in 178 patients with AIDS wasting. The
study participants had unintentional weight loss of at least 10% or weighed
less than 90% of the lower limit of ideal body weight. In the 140 evaluable
patients (those completing a 12-week course of treatment and who were at least
80% compliant with study drug; Serostim® = 69, Placebo = 71),
the mean difference in weight increase in the Serostim®-treated
group was 1.6 kg (3.5 lb.). For those patients that had a week two assessment,
76% had weight gain. After 12 weeks of treatment, 74% of the patients treated
with Serostim® gained weight while only 48% of the placebo-treated
patients gained weight (p=0.002). Mean differences in lean body mass change
between the Serostim® treated group and the placebo treated group
was 3.1 kg (6.8 lbs) as measured by DEXA. Significant lean body mass gain (p<0.05)
was achieved in 70% of the patients treated with Serostim® after
12 weeks (see Table 1). No change in LBM was observed in placebo-treated patients.
Mean increase in weight and lean body mass and mean decrease in body fat (see
Figure 1) were significantly greater in the Serostim® treated
group than in the placebo group (p=0.011, p<0.001, p<0.001, respectively).
While depletion of body weight and lean body mass has been associated with increased
morbidity and mortality, the clinical significance of treatment-induced weight
gain and LBM accrual has yet to be established.
Treatment with Serostim® resulted in a significant
increase of 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® (see Figure 2). There was no improvement
in the placebo treated group at 12 weeks. Changes in treadmill performance were
significantly correlated with changes of lean body mass.
The most common reason for patient drop-out was concurrent
medical events including opportunistic infections. There were decreases in serum
albumin in both Serostim® and placebo groups. There was up to
a 2.7 fold increase in serum IGF-1 levels. No patients developed antibodies
to growth hormone.
Patients completing the 12-week placebo-controlled portion
of the study were eligible to receive open-label Serostim® therapy,
and 96% (n=136) chose to participate. Since this phase of the trial was open-label,
and due to limited numbers of evaluable patients, it is difficult to interpret
weight and LBM changes. The patients who initially received placebo had significant
increases in median weight (1.4 kg, p=0.012) and lean body mass (2.4 kg, p<0.001)
compared to baseline, during their first 12-weeks on Serostim®.
These changes were similar in magnitude to those observed in patients initially
treated with Serostim®. For those patients who had initially
received Serostim® in the placebo-controlled trials, the median
weight change during 12-weeks of open label treatment with Serostim®
(-0.2 kg) and LBM change (-0.3 kg) were not significant (p=0.700 and p=0.661,
respectively), suggesting that the gains of weight and LBM were not lost.
Table 1: Trial 1: Change from Baseline of LBM 12-Week Efficacy
Results
| |
Serostim®
|
Placebo
|
| |
n
|
Results
|
n
|
Results
|
|
Lean Body Mass (kg)
|
69
|
+3.1*
|
69
|
-0.1
|
|
LBM Responders¥
|
69
|
70%*
|
69
|
12%
|
¥ Major LBM response defined
as >4% increase of LBM
* Statistically significantly different from placebo at
p<0.05
Clinical Trial 2: Additional efficacy and safety parameters
were evaluated in a second multicenter, double-blind, placebo-controlled study
comparing Serostim®, 6 mg/day administered subcutaneously vs.
placebo, in AIDS patients with wasting enrolled 177 patients who were randomized
in a 2:1 ratio, to receive Serostim® or placebo. In the 78 evaluable
patients (those completing a 12-week course of treatment and who were at least
80% compliant with study drug), there was a mean increase in body weight of
1.6 kg, but this change was not significant compared to placebo (p=0.110). The
most common reason for patient drop-out was concurrent medical events including
opportunistic infections.
Patients were asked to respond to a nine item survey that measured
subjective assessments of treatment. Positive findings at 6 and 12 weeks were
observed in two of the nine items (change in appearance and overall benefit
of treatment). Results of other measures were inconclusive.
Survival Analyses: The two placebo-controlled clinical trials
of Serostim® in patients with AIDS wasting up to 12 weeks in
length found no difference in survival between groups.
Clinical Trial 3: A third open-label, baseline-controlled,
multicenter study conducted in Europe administering Serostim®,
6 mg/day subcutaneously, enrolled 24 patients with AIDS wasting. Twenty patients
completed the 12-week treatment regimen and had body composition measurements
using bioimpedance analysis. The mean increase over baseline for body weight
was 1.6 kg (p=0.137, NS) and for lean body mass was 2.3 kg (p=0.037).
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