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Somavert (Pegvisomant) - Description and Clinical Pharmacology



SOMAVERT contains pegvisomant for injection, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist.

Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000, and 52,000 Daltons. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay.

SOMAVERT is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection, USP. SOMAVERT is available in single-dose sterile vials containing 10, 15, or 20 mg of pegvisomant protein (approximately 10, 15, and 20 U activity, respectively). Vials containing 10, 15, and 20 mg of pegvisomant protein correspond to approximately 21, 32, and 43 mg pegvisomant, respectively. Each vial also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate.

SOMAVERT is supplied in packages that include a plastic vial containing diluent. Sterile Water for Injection, USP, is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, and is supplied in single-dose containers to be used as a diluent.



Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. Inhibition of GH action results in decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other GH-responsive serum proteins, including IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS).


Absorption:    Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose.

Distribution:    The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (Cmax, AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively.

Metabolism and Elimination:    The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life of approximately 6 days following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans.


In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known (see PRECAUTIONS, Drug Interactions).


Renal:    No pharmacokinetic studies have been conducted in patients with renal insufficiency.

Hepatic:    No pharmacokinetic studies have been conducted in patients with hepatic insufficiency.

Geriatric:    No pharmacokinetic studies have been conducted in elderly subjects.

Pediatric:    No pharmacokinetic studies have been conducted in pediatric subjects.

Gender:    No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis.

Race:    The effect of race on the pharmacokinetics of pegvisomant has not been studied.


One hundred twelve patients with acromegaly previously treated with surgery, radiation therapy, and/or medical therapies participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and SOMAVERT. Following withdrawal from previous medical therapy, the 80 patients randomized to treatment with SOMAVERT received a subcutaneous (SC) loading dose, followed by 10, 15, or 20 mg/day SC. The three groups that received SOMAVERT showed dose-dependent reductions in serum levels of IGF-I, free IGF-I, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1 and Table 1).

Figure 1. Effects of SOMAVERT on Serum Markers
(Mean ± Standard Error)

After 12 weeks of treatment, serum IGF-I levels were normalized in 10%, 39%, 75%, and 82% of subjects treated with placebo, 10, 15, or 20 mg/day of SOMAVERT, respectively (Figure 2).

Figure 2. Percent of Patients Whose IGF-I Levels
Normalized at Week 12

Table 2 shows the effect of treatment with SOMAVERT on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on both the total and individual scores for signs and symptoms of acromegaly. Each individual score (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7.

Table 1. Mean Percent Change from Baseline in IGF-I at Week 12 for Intent-to-Treat Population
  SOMAVERT Placebo n=31
  10 mg/day n=26 15 mg/day n=26 20 mg/day n=28
Mean percent change from
baseline in IGF-1 (SD)
-27 (28) -48 (26) -63 (21) -4.0 (17)
SOMAVERT minus Placebo
(95% CI for treatment difference)
-23 *
(-35, -11)
-44 *
(-56, -33)
-59 *
(-68, -49)
* P<0.01

Table 2. Mean Change from Baseline (SD) at Week 12 for Ring Size and Signs and Symptoms of Acromegaly
  SOMAVERT Placebo n=30
  10 mg/day n=26 15 mg/day n=24-25 20 mg/day n=26-27
Ring size -0.8 (1.6) -1.9 (2.0) -2.5 (3.3) -0.1 (2.3)
Total score for signs and
symptoms of acromegaly
-2.5 (4.3) -4.4 (5.9) -4.7 (4.7) 1.3 (6.0)
     Soft-tissue swelling -0.7 (1.6) -1.2 (2.3) -1.3 (1.3) 0.3 (2.3)
     Arthralgia -0.3 (1.8) -0.5 (2.5) -0.4 (2.1) 0.1 (1.8)
     Headache -0.4 (1.6) -0.3 (1.4) -0.3 (2.0) 0.1 (1.7)
     Perspiration -0.6 (1.6) -1.1 (1.3) -1.7 (1.6) 0.1 (1.7)
     Fatigue -0.5 (1.4) -1.3 (1.7) -1.0 (1.6) 0.7 (0.5)

Ring size at week 12 was smaller (improved) in the groups treated with 15 or 20 mg of SOMAVERT, compared with placebo. The mean total score for signs and symptoms at week 12 was lower (improved) in each of the groups treated with SOMAVERT, compared with the group treated with placebo.

Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant (see PRECAUTIONS Drug/Laboratory Test Interactions), rise within two weeks of beginning treatment with SOMAVERT. The largest GH response was seen in patients treated with doses of SOMAVERT greater than 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of SOMAVERT followed by a fixed daily dose, this rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations also remained stable in patients treated with SOMAVERT for up to 18 months.

Another cohort of 38 patients with acromegaly was treated with SOMAVERT in a long-term, open-label, dose-titration study and received at least 12 consecutive months of daily dosing with SOMAVERT (mean = 55 weeks). The mean (± standard deviation) IGF-I concentration at baseline in this cohort was 917 (± 356) ng/mL after withdrawal from previous medical therapy, falling to 268 (± 134) ng/mL at the end of treatment with SOMAVERT. Thirty-five of the 38 patients (92%) achieved a normal (age-adjusted) IGF-I concentration. After the first visit at which a normal IGF-I concentration was observed, IGF-I levels remained within the normal range at 92% of all subsequent visits over a mean duration of one year.

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