Mechanism of Action
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).
Pharmacokinetics
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.
Drug-Drug Interactions
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).
Special Populations
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.