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

Johannes D Veldhuis, Martin Bidlingmaier, Joy Bailey, Dana Erickson, Paola Sandroni

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. Rationale: 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. Hypothesis: 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. Methods: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). Outcomes: Median (range) concentrations of pegvisomant in serum were 215 (74-539) μg/liter and in CSF 0.035 (0.010-0.28) μg/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 μg/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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)3844-3847
Number of pages4
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number8
DOIs
StatePublished - Aug 2010

Fingerprint

Cerebrospinal fluid
Somatotropin Receptors
Hormone Antagonists
Cerebrospinal Fluid
Brain
Blood-Brain Barrier
Serum
Assays
Median Eminence
Choroid Plexus
Extracellular Fluid
Neurology
pegvisomant
Insulin-Like Growth Factor I
Cerebral Cortex
Hypothalamus
Hippocampus
Blood
Central Nervous System
Feedback

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans. / Veldhuis, Johannes D; Bidlingmaier, Martin; Bailey, Joy; Erickson, Dana; Sandroni, Paola.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 8, 08.2010, p. 3844-3847.

Research output: Contribution to journalArticle

Veldhuis, Johannes D ; Bidlingmaier, Martin ; Bailey, Joy ; Erickson, Dana ; Sandroni, Paola. / A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 8. pp. 3844-3847.
@article{4cc0071afdc14f92bc46536c0a4d7908,
title = "A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans",
abstract = "Background: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. Rationale: 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. Hypothesis: 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. Methods: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). Outcomes: Median (range) concentrations of pegvisomant in serum were 215 (74-539) μg/liter and in CSF 0.035 (0.010-0.28) μg/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 μg/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. Conclusions: 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.",
author = "Veldhuis, {Johannes D} and Martin Bidlingmaier and Joy Bailey and Dana Erickson and Paola Sandroni",
year = "2010",
month = "8",
doi = "10.1210/jc.2010-0538",
language = "English (US)",
volume = "95",
pages = "3844--3847",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "8",

}

TY - JOUR

T1 - A pegylated growth hormone receptor antagonist, pegvisomant, does not enter the brain in humans

AU - Veldhuis, Johannes D

AU - Bidlingmaier, Martin

AU - Bailey, Joy

AU - Erickson, Dana

AU - Sandroni, Paola

PY - 2010/8

Y1 - 2010/8

N2 - Background: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. Rationale: 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. Hypothesis: 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. Methods: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). Outcomes: Median (range) concentrations of pegvisomant in serum were 215 (74-539) μg/liter and in CSF 0.035 (0.010-0.28) μg/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 μg/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. Conclusions: 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.

AB - Background: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. Rationale: 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. Hypothesis: 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. Methods: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). Outcomes: Median (range) concentrations of pegvisomant in serum were 215 (74-539) μg/liter and in CSF 0.035 (0.010-0.28) μg/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 μg/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. Conclusions: 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.

UR - http://www.scopus.com/inward/record.url?scp=77955357712&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955357712&partnerID=8YFLogxK

U2 - 10.1210/jc.2010-0538

DO - 10.1210/jc.2010-0538

M3 - Article

C2 - 20444908

AN - SCOPUS:77955357712

VL - 95

SP - 3844

EP - 3847

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 8

ER -