Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

Christoffer Wenzel Tornøe, Henrik Agersø, Henrik Aalborg Nielsen, Henrik Madsen, E. Niclas Jonsson

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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.
    Original languageEnglish
    JournalPharmaceutical Research
    Volume21
    Issue number4
    Pages (from-to)574-584
    ISSN0724-8741
    DOIs
    Publication statusPublished - 2004

    Keywords

    • Degarelix
    • NONMEM
    • Population pharmacokinetic modeling
    • Prostate cancer
    • Subcutaneous depot

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