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Research ArticleDrug Discovery and Translational Medicine

Pharmacokinetic/Pharmacodynamic Model of the Testosterone Effects of Triptorelin Administered in Sustained Release Formulations in Patients with Prostate Cancer

Elba Romero, Nieves Vélez de Mendizabal, Josep-María Cendrós, Concepción Peraire, Emma Bascompta, Rosendo Obach and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 788-798; DOI: https://doi.org/10.1124/jpet.112.195560
Elba Romero
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Nieves Vélez de Mendizabal
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Josep-María Cendrós
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Concepción Peraire
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Emma Bascompta
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Rosendo Obach
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Iñaki F. Trocóniz
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (E.R., N.V.d.M., I.F.T.); and Drug Metabolism and Pharmacokinetics, Ipsen Pharma S.A., Barcelona, Spain (J.-M.C., C.P., E.B., R.O.)
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Abstract

The objectives of the current work were to develop a predictive population pharmacokinetic (PK)/pharmacodynamic (PD) model for the testosterone (TST) effects of triptorelin (TRP) administered in sustained-release (SR) formulations to patients with prostate cancer and determine the minimal required triptorelin serum concentration (CTRP_min) to keep the testosterone levels of the patients below or equal to the level of castration (TST ≤0.5 ng/ml). A total of eight healthy male volunteers and 74 patients with prostate cancer received one or two doses of triptorelin injected subcutaneously or intramuscularly. Five different triptorelin formulations were tested. Pharmacokinetic (serum concentration of triptorelin) and pharmacodynamic (TST levels in serum) data were analyzed by using the population approach with NONMEM software (http://www.iconplc.com/technology/products/nonmem/). The PK/PD model was constructed by assembling the agonist nature of triptorelin with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible for the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of KD, the receptor equilibrium dissociation constant of triptorelin, and CTRP_min to keep 95% of the patients castrated were 0.931 and 0.0609 ng/ml, respectively. The semimechanistic nature of the model renders the predictions of the effect of triptorelin on TST possible regardless the type of SR formulation administered, while exploring different designs during the development of new delivery systems.

Footnotes

  • This work was supported by Ipsen Pharma S.A. Barcelona, Spain. E.R. received a Ph.D studentship from the Consejo Nacional de Ciencia y Tecnologia from the Mexican government [Grant 207500]. N.V.M. received a postdoctoral fellowship from the Department of Pharmacy and Pharmaceutical Technology of the University of Navarra, Pamplona, Spain. I.F.T. has received financial research support from Ipsen Pharma S.A.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195560.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    TST
    testosterone
    TST0
    level of testosterone at baseline
    AGN
    ratio between the endogenous agonist concentration and its receptor equilibrium dissociation constant
    BGN
    ratio between serum concentrations of triptorelin and its receptor equilibrium dissociation constant
    CI
    confidence interval
    CL
    clearance
    Conc
    concentration
    CTRP_min
    minimum required triptorelin serum concentrations to maintain the patient castrated
    TTRP_min
    time during which triptorelin levels are equal or higher than CTRP_min
    FRAC
    fraction of activated receptors
    FRAC_0
    fraction of activated receptors at baseline
    kS_T
    zero-order rate constant of testosterone synthesis
    RT
    total amount of receptors
    DR_50
    value of the difference between FRAC and FRAC_0 that elicits a 50% of maximum reduction in kS_R for a given amount of RT
    FABS
    absolute bioavailability
    FSH
    follicle-stimulating hormone
    LH
    luteinizing hormone
    kin
    zero-order rate of testosterone production independent from LH and FSH
    GnRH
    gonadotropin-releasing hormone
    IIV
    interindividual variability
    KD
    receptor equilibrium dissociation constant of triptorelin
    kS_R
    zero-order rate constant of receptor synthesis
    kD_R
    first-order rate constant of receptor degradation
    kD_T
    first-order rate constant of testosterone degradation
    PD
    pharmacodynamic
    PK
    pharmacokinetic
    RAC
    amount of activated receptors
    RAC_0
    amount of activated receptors at baseline
    RMSE
    root mean squared error
    RT_0
    total amount of receptors at baseline
    SR
    sustained release
    TRP
    triptorelin.

  • Received April 12, 2012.
  • Accepted June 11, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 3
1 Sep 2012
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Research ArticleDrug Discovery and Translational Medicine

PK/PD Model of Triptorelin in Patients with Prostate Cancer

Elba Romero, Nieves Vélez de Mendizabal, Josep-María Cendrós, Concepción Peraire, Emma Bascompta, Rosendo Obach and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 788-798; DOI: https://doi.org/10.1124/jpet.112.195560

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Research ArticleDrug Discovery and Translational Medicine

PK/PD Model of Triptorelin in Patients with Prostate Cancer

Elba Romero, Nieves Vélez de Mendizabal, Josep-María Cendrós, Concepción Peraire, Emma Bascompta, Rosendo Obach and Iñaki F. Trocóniz
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 788-798; DOI: https://doi.org/10.1124/jpet.112.195560
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