Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Other anterior pituitary lobe hormones and analogues, ATC code: H01AX01.


Mechanism of action

Pegvisomant is an analogue of human growth hormone that has been genetically modified to be a growth hormone receptor antagonist. Pegvisomant binds to growth hormone receptors on cell surfaces, where it blocks growth hormone binding, and thus interferes with intracellular growth hormone signal transduction. Pegvisomant is highly selective for the GH receptor, and does not cross-react with other cytokine receptors, including prolactin.

Pharmacodynamic effects

Inhibition of growth hormone action with pegvisomant leads to decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other growth hormone-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3).

Clinical efficacy and safety

Acromegalic patients (n=112) have been treated in a 12-week, randomised, double-blind, multicentre study comparing placebo and pegvisomant. Dose-dependent, statistically significant reductions in mean IGF-I (p<0.0001), free IGF-I (p<0.05), IGFBP-3 (p<0.05) and ALS (p<0.05) were observed at all post-baseline visits in the pegvisomant treatment groups. The serum IGF-1 was normalised at the end of the study (week 12) in 9.7%, 38.5%, 75% and 82% of subjects treated with placebo, 10 mg/day, 15 mg/day or 20 mg/day pegvisomant respectively.

Statistically significant differences from placebo (p<0.05) were observed for improvements in the total signs and symptoms score for all dose groups compared to placebo.

A cohort of 38 acromegalic subjects has been followed in a long-term, open-label, dose-titration study for at least 12 consecutive months of daily dosing with pegvisomant (mean = 55 weeks). The mean IGF-I concentration in this cohort fell from 917 ng/ml to 299 ng/ml on pegvisomant, with 92% achieving a normal (age-adjusted) IGF-I concentration.

In different studies and also in Acrostudy, pegvisomant normalised IGF-1 levels in a high percentage of patients (>70%) and significantly decreased fasting plasma glucose (FPG) and fasting plasma insulin (FPI) levels.

Pegvisomant also improves insulin sensitivity, this is likely due to a blockade of the GH receptors on tissues, mainly the liver and also adipose tissue, kidneys, and skeletal muscles, thereby removing the detrimental effect of GH on insulin signaling, lipolysis, and gluconeogenesis. However, the mechanism of action of all these effects is not known with certainty. A decrease in doses of insulin or hypoglycaemic medicinal products may be needed in acromegalic patients with diabetes mellitus (see sections 4.4 and 4.5).

Pharmacokinetic Properties

5.2. Pharmacokinetic properties

Absorption
Absorption of pegvisomant following subcutaneous administration is slow and prolonged, and peak serum pegvisomant concentrations are not generally attained until 33-77 hours after administration. The mean extent of absorption of a subcutaneous dose was 57% relative to an intravenous dose.

Distribution

The apparent volume of distribution of pegvisomant is relatively small (7-12 L).
Biotransformation

The metabolism of pegvisomant has not been studied.

Elimination
The mean total body systemic clearance of pegvisomant following multiple doses is estimated to be 28 ml/h for subcutaneous doses ranging from 10 to 20 mg/day. Renal clearance of pegvisomant is negligible and accounts for less than 1% of total body clearance. Pegvisomant is slowly eliminated from serum, with mean estimates of half-life generally ranging from 74 to 172 hours following either single or multiple-doses.

Linearity/non-linearity

After single subcutaneous pegvisomant administration no linearity is observed with rising doses of 10, 15 or 20 mg. Approximately linear pharmacokinetics is observed at steady state in the population pharmacokinetic studies. The data from 145 patients in two long-term studies who received daily doses of 10, 15, or 20 mg, demonstrate pegvisomant mean serum concentrations (± SD) of approximately 8800 ± 6300, 13200 ± 8000 and 15600 ± 10300 ng/ml, respectively.

The pharmacokinetics of pegvisomant are similar in normal healthy volunteers and acromegaly patients, although heavier individuals tend to have a higher total body clearance of pegvisomant than lighter individuals, and may thus require greater doses of pegvisomant.