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.
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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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