Bioequivalence studies for three formulations of a recombinant human growth hormone: Challenges and lessons learned.
Summary of "Bioequivalence studies for three formulations of a recombinant human growth hormone: Challenges and lessons learned."
Two bioequivalence (BE) studies in healthy volunteers comparing new formulations of the recombinant human growth hormone (rhGH) Nutropin AQ (somatropin [rDNA origin] injection; Genentech, Inc., South San Francisco, CA) with the currently marketed formulation (5mg/mL) were conducted to extend available dosing options. All formulations were administered by subcutaneous (SC) injection ranging in volume from 0.25 to 1.0mL depending on the formulation concentration. Study A was a 2-period crossover design to assess the BE of 5 and 10mg/mL. The estimate for relative bioavailability (AUC(0-24h)) was within the prespecified BE interval (0.80-1.25). However, while the C(max) estimate (1.17) was contained within the range for BE, the 90% CI (0.986-1.38) extended beyond the prespecified BE interval. As a result, Study A failed to show BE between the 5 and 10mg/mL formulations. Review of the data showed unexpected increased variability in the observed C(max). Further review of individual data suggested that in 4 subjects, the GH concentration profile of 1 of the 2 injections closely resembled the absorption kinetics of an intramuscular injection rather than an SC injection. Because study conduct may have contributed to these results, we performed a second study, Study B. This study incorporated injection technique training, a defined injection site, and a larger sample size to accommodate variability. It also included a third formulation, creating a 3-period crossover design to assess the BE of 2.5, 5, and 10mg/mL. Study B results demonstrated BE of the new 2.5- and 10-mg/mL formulations to the reference 5-mg/mL formulation, and BE to each other, with all 90% CIs within the BE range of 0.80 to 1.25. Thus the challenge of recognizing that design issues could affect outcomes gave us the tools to perform a second study, and the positive results taught us that demonstrating BE is an issue not only of pharmacology, but also of study methodology and execution.
This article was published in the following journal.
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20708421
- DOI: http://dx.doi.org/10.1016/j.ghir.2010.07.002
Medical and Biotech [MESH] Definitions
Human Growth Hormone
A 191-amino acid polypeptide hormone secreted by the human adenohypophysis (PITUITARY GLAND, ANTERIOR), also known as GH or somatotropin. Synthetic growth hormone, termed somatropin, has replaced the natural form in therapeutic usage such as treatment of dwarfism in children with growth hormone deficiency.
A form of dwarfism caused by complete or partial GROWTH HORMONE deficiency, resulting from either the lack of GROWTH HORMONE-RELEASING FACTOR from the HYPOTHALAMUS or from the mutations in the growth hormone gene (GH1) in the PITUITARY GLAND. It is also known as Type I pituitary dwarfism. Human hypophysial dwarf is caused by a deficiency of HUMAN GROWTH HORMONE during development.
Growth Hormone-secreting Pituitary Adenoma
A pituitary tumor that secretes GROWTH HORMONE. In humans, excess HUMAN GROWTH HORMONE leads to ACROMEGALY.
The biologically active fragment of human growth hormone-releasing factor, consisting of GHRH(1-29)-amide. This N-terminal sequence is identical in several mammalian species, such as human, pig, and cattle. It is used to diagnose or treat patients with GROWTH HORMONE deficiency.
An autosomal recessive disorder characterized by short stature, defective GROWTH HORMONE RECEPTOR, and failure to generate INSULIN-LIKE GROWTH FACTOR I by GROWTH HORMONE. Laron syndrome is not a form of primary pituitary dwarfism (GROWTH HORMONE DEFICIENCY DWARFISM) but the result of mutation of the human GHR gene on chromosome 5.
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