Preclinical and clinical in vitro in vivo correlation of an hGH dextran microsphere formulation.
OBJECTIVE
To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers.


METHODS
A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study).


RESULTS
Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7-8 days) in hGH serum concentrations (peak concentrations: 1-2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres.


CONCLUSIONS
Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.
Vlugt-Wensink
K D F
KD
OctoPlus Technologies, OctoPlus b.v., Zernikedreef 12, 2333 CL, Leiden, The Netherlands. Wensink@octoplus.nl
de Vrueh
R
R
Gresnigt
M G
MG
Hoogerbrugge
C M
CM
van Buul-Offers
S C
SC
de Leede
L G J
LG
Sterkman
L G W
LG
Crommelin
D J A
DJ
Hennink
W E
WE
Verrijk
R
R
D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D049628:Body Size / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D003911:Dextrans / Q000737:chemistry*; D004195:Disease Models, Animal; D004337:Drug Carriers; D004339:Drug Compounding; D004392:Dwarfism / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008817:Mice, Mutant Strains; D008863:Microspheres; D008875:Middle Aged; D008954:Models, Biological; D010316:Particle Size; D012995:Solubility; D050817:Transcription Factor Pit-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D003692:Delayed-Action Preparations; D003911:Dextrans; D004337:Drug Carriers; D019382:Human Growth Hormone; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D008689:Methacrylates; D050817:Transcription Factor Pit-1; C515497:IGFBP3 protein, human; C494185:Pou1f1 protein, mouse; C508284:dextran hydroxyethyl methacrylate