Long-acting injectables (LAIs) offer the promise of better efficacy and tolerability, compared to oral drugs due to improved adherence and more stable pharmacokinetics. However, data on LAIs has been mixed, with some studies finding that they are more effective and tolerable while others report findings to the contrary. One key advantage of LAIs is that a target therapeutic window can be more easily achieved using the controlled release mechanism. However, the central disadvantage of LAIs is the exceedingly large inter-individual pharmacokinetic variability. As numerous LAI formulations are going off-patent, opportunities for the development of generic medications are increasing. The guidelines to demonstrate bioequivalence (BE) between a generic product and a competitor require a clear definition to assist in the development of generic LAI products. Unfortunately, the presence of the large inter-individual variability in LAIs makes these thresholds difficult to attain. Leuprolide acetate (Lupron depot) is a frequently used LAI; it is expensive, and there is no generic formulation. Lupron is used clinically for treatment of endometriosis, uterine leiomyoma, central precocious puberty, and palliative treatment of advanced prostatic cancer. Leuprolide acetate is a nonapeptide gonadotropin-releasing hormone receptor (GnRHR) agonist, used to modify an individual's hormone profile. Specifically, leuprolide acetate binds to the GnRHR in the anterior pituitary with a greater affinity than GnRH causing an initial burst release of leutinizing hormone (LH) and follicle-stimulating hormone (FSH). However, over time, leuprolide acetate administration will desensitize the GnRHR, decreasing the release of LH and FSH, and therefore the concentrations of those hormones and estradiol and testosterone in systemic circulation. The objective of this proposal is to use Lupron as a prototypical LAI to develop pharmacometric and simulation methodology to enable bioequivalence assessment. This study will collect data from patients who are being treated with Lupron for a variety of indications. Changes in baseline LH and FSH will be used as markers for the PD effects of Lupron. Patient samples will be analyzed for concentrations of Lupron (for pharmacokinetic (PK) assessment), LH and FSH, gonadal steroids (i.e., testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females), and natal hormone levels (for pharmacodynamic (PD) assessment). Time course of action will be used as a marker of BE. This study will perform population PK/PD modeling and statistical analysis. This will develop and demonstrate methodology to facilitate statistical BE assessment of any LAI agents based upon comparative similarity of intended response (PD) which ultimately serves as the basis for BE evaluation. Thus, utilizing a readily available and frequently utilized agent, Lupron, will enable the development of bioequivalent PD methodology to aid in the process of defining the methodology for benchmark regulatory decisions.

Public Health Relevance

Long-acting injectable (LAIs) are increasingly used in the clinical setting substantiating a growing need for guidance with regard to LAI bioequivalence (BE) for the assessment of generic formulations qualitatively and quantitatively against their referenced drug. Pharmacometric modeling and simulation in addition to statistical methods can provide valuable tools to evaluate BE and inform the understanding of brand to generic drug substitution. The results of this proposal will provide regulators with improved methods that can be used to asses LAIs while providing a methodology to examine other important LAIs with similar complexities.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZFD1)
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Fang, Lanyan
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University of Utah
Schools of Medicine
Salt Lake City
United States
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