A Semi-Mechanistic Integrated Pharmacokinetic/Pharmacodynamic Model of the Testosterone Effects of the Gonadotropin-Releasing Hormone Agonist Leuprolide in Prostate Cancer Patients

Lim, Chay Ngee; Salem, Ahmed Hamed

doi:10.1007/s40262-015-0251-9

Cited by 6 publications

(12 citation statements)

References 32 publications

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“…The effects of both DEX and SUL were characterized by Hill's function with the E max (or I max ) fixed to 1, because the model failed to perform well when E max (or I max ) was estimated, possibly due to limitations in the observed data. Then, assumptions were made that tumor growth would be completely inhibited and remain stagnant when the maximum effect of DEX is achieved and that its sensitivity to DEX would be maximized when the maximum effect of SUL is reached, which is also seen in other publications [25,26].…”

Section: Discussionmentioning

confidence: 99%

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Yao

Chen

et al. 2019

Acta Pharmacol Sin

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Previous studies show that dopamine D 2 -like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg −1 ·d −1 ) or SUL (25, 50 mg·kg −1 ·d −1 ) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill’s function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC 50 . The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.

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Section: Discussionmentioning

confidence: 99%

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Yao

Chen

et al. 2019

Acta Pharmacol Sin

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“…However, it could not describe the rapid increase and decrease of testosterone. The population PK–PD model of leuprolide in prostate cancer patients developed by Lim and Salem [ 19 ] is useful and applicable in clinical situations for personalized medicine. On the other hand, our model focused on the use of the PK–PD model as an evaluation tool during the development process of new formulations such as SR injectable depot formulation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats

et al. 2018

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This study developed the pharmacokinetic (PK)–pharmacodynamic (PD) model of the testosterone-suppressive effect of leuprolide for evaluation of the sustained release (SR) depot and leuprolide solution in rats with or without prostate cancer. Six groups of rats were divided by the routes of administration (intravenous and subcutaneous injection) and kinds of formulation (vehicle, leuprolide solution, and SR depot). The PK profile after subcutaneous injection of leuprolide solution could be well-described by the one-compartment model. The absorption rate constant, the total body clearance, and the volume of distribution were estimated at 16.67 h−1, 514.46 mL/h, and 487.40 mL. Using PK parameters in the solution-administered group, the PK model for the SR depot was developed. The PK–PD model was constructed by describing the testosterone-suppressive effect of leuprolide using the feedback turnover model. The response of testosterone after administration of each formulation was well described using this PK–PD model for the estimation of PD parameters (EC50, Emax, h) and systemic parameters (kin, kout, kf on, kf off). The developed PK–PD model containing an inhibitory feedback system could successfully describe the testosterone-suppressive effect of leuprolide in the type of formulation. The PK–PD model developed would be useful for evaluating the formulation of similar drugs whose effect is regulated through the feedback mechanism.

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“…There are many clinical reports about the optimization of the dose regimen, including the dose based on the body size to a flat dose, in the past 5 years. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] There are 3 ways to optimize the dose regimen in general: (1) exposure modification, (2) usage of the exposureresponse curve, and (3) prediction of the efficacy or safety endpoint directly. When the drug efficacy and safety profiles have already been established (eg, optimization for children with a significant amount of adult data), only exposure modification tends to be selected.…”

Section: Discussionmentioning

confidence: 99%

Dosage Optimization of Nemolizumab Using Population Pharmacokinetic and Pharmacokinetic‐Pharmacodynamic Modeling and Simulation

Saito¹,

Iida²,

Terao³

et al. 2017

The Journal of Clinical Pharma

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Nemolizumab is a humanized anti-interleukin-31 receptor A monoclonal antibody for treating atopic dermatitis, and it especially improves pruritus. The objective of the simulation study was to optimize the dose regimen using a flat dose. The serum nemolizumab concentration and pruritus visual analog scale as an efficacy end point were modeled using the population analysis approach in 299 patients with atopic dermatitis who received placebo or doses between 0.1 and 3 mg/kg as a single dose once every 4 weeks or 2 mg/kg once every 8 weeks. A 1-compartment model with first-order absorption was employed as the pharmacokinetic model. An indirect turnover model with an inhibition component was employed as the main part of the pharmacokinetic-pharmacodynamic model. The models well described the observations. Therefore, simulations with several dose regimens were performed to optimize the dose regimen including a flat dose. The simulated area under the concentration-time curve at a steady state around 75 mg in the every-4-week regimen corresponds to that associated with the dose range of 0.5 to 2 mg/kg in the 4-week regimen. The simulated pruritus visual analog scale also showed a similar tendency. These simulation results support dose optimization during the clinical development program of nemolizumab.

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A Semi-Mechanistic Integrated Pharmacokinetic/Pharmacodynamic Model of the Testosterone Effects of the Gonadotropin-Releasing Hormone Agonist Leuprolide in Prostate Cancer Patients

Cited by 6 publications

References 32 publications

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats

Dosage Optimization of Nemolizumab Using Population Pharmacokinetic and Pharmacokinetic‐Pharmacodynamic Modeling and Simulation

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