A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans

GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback.

Pegvisomant is a recombinant mutated GH molecule with high affinity, but little or no activating capability, for the GH receptor. It is used clinically as a GH antagonist.

Systemic pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors, thereby allowing for antagonism of central actions of GH. SUBJECTS AND LOCATION: Six adults requiring a cerebrospinal fluid (CSF) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center.

Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg).

Median (range) concentrations of pegvisomant in serum were 215 (74-539) microg/liter and in CSF 0.035 (0.010-0.28) microg/liter (P=0.016). CSF drug levels were indistinguishable from assay threshold. Corresponding GH values were 0.29 (0.010-1.3) in serum and 0.075 microg/liter (0.01-0.13) in CSF. The geometric mean ratios of serum/CSF pegvisomant and GH concentrations were 5116:1 and 3.5:1, respectively, thus defining a more than 1400-fold difference between mutated and natural GH.

Based upon CSF measurements, a pegylated GH-receptor antagonist does not cross the human blood-brain barrier, thereby sparing inhibition of central nervous system GH actions. Thus, the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier, such as via the median eminence and/or via suppression of IGF-I concentrations.