Preclinical and Clinical In Vitro In Vivo Correlation of an hGH Dextran Microsphere Formulation

• Published in: Pharmaceutical research Vol. 24; no. 12; pp. 2239 - 2248
• Main Authors: Vlugt-Wensink, K. D. F., de Vrueh, R., Gresnigt, M. G., Hoogerbrugge, C. M., van Buul-Offers, S. C., de Leede, L. G. J., Sterkman, L. G. W., Crommelin, D. J. A., Hennink, W. E., Verrijk, R.
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.12.2007; Springer Nature B.V; Springer US
• Subjects: Aged; Animals; Biological and medical sciences; Biomarkers - blood; Biomedical research; Blood tests; Body Size - drug effects; Body Weight - drug effects; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dextrans - chemistry; Disease Models, Animal; Drug Carriers; Drug Compounding; Dwarfism - drug therapy; Dwarfism - genetics; Dwarfism - physiopathology; General pharmacology; Hormones; Human Growth Hormone - administration & dosage; Human Growth Hormone - blood; Human Growth Hormone - chemistry; Human Growth Hormone - pharmacokinetics; Human Growth Hormone - pharmacology; Human subjects; Humans; Injections, Subcutaneous; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins - blood; Insulin-Like Growth Factor I - metabolism; Male; Medical sciences; Methacrylates - chemistry; Mice; Mice, Mutant Strains; Microspheres; Middle Aged; Models, Biological; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology; Pharmacology. Drug treatments; Research Paper; Rodents; Solubility; Transcription Factor Pit-1 - deficiency; Transcription Factor Pit-1 - genetics; Transcription Factor Pit-1 - metabolism; Correlation; Microsphere; Pharmaceutical technology; Preclinical trial; hGH; In vitro; Dextran; dex-HEMA microspheres; In vivo; Blood substitute; Formulation; in vitro in vivo correlation; Microparticle
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-007-9433-y

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