Journal article
Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix
Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose-concentration dependent absorption.
Methods. The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical depot. The dose-volume effect on the SC release is estimated using a B-spline basis whereas the bioavailability is modeled as a function of the dose-concentration.
Results. The SC depot model is approximated by using two concentric spherical compartments for the SC absorption combined with a two-compartment disposition model. The results indicate that the volume effect is most apparent at low injection volumes whereas the effect is diminishing at higher injection volumes.
The dose-concentration effect on the bioavailability is estimated to decrease at increasing dose-concentrations. Conclusions. The presented SC depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles.
Language: | English |
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Publisher: | Kluwer Academic Publishers-Plenum Publishers |
Year: | 2004 |
Pages: | 574-584 |
Journal subtitle: | An Official Journal of the American Association of Pharmaceutical Scientists |
ISSN: | 1573904x and 07248741 |
Types: | Journal article |
DOI: | 10.1023/B:PHAM.0000022403.60314.51 |
ORCIDs: | Madsen, Henrik |
Degarelix NONMEM Population pharmacokinetic modeling Prostate cancer SDG 3 - Good Health and Well-being Subcutaneous depot
Biochemistry, general Biomedical Engineering Biomedicine Delayed-Action Preparations Dose-Response Relationship, Drug Gonadotropin-Releasing Hormone Humans Injections, Subcutaneous Male Medical Law Models, Biological Oligopeptides Pharmacology/Toxicology Pharmacy acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide degarelix population pharmacokinetic modeling prostate cancer subcutaneous depot.