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.

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Journal Details

This article was published in the following journal.

Name: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Socie
ISSN: 1532-2238
Pages:

Links

• PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20708421
• DOI: http://dx.doi.org/10.1016/j.ghir.2010.07.002