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

Lee, Dong‐Seok; Kim, Sook-Jin; Choi, Go-Wun; Lee, Yong-Bok; Cho, Hea-Young

doi:10.3390/molecules23040909

Cited by 5 publications

(5 citation statements)

References 19 publications

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“…As a result, testosterone secretion is suppressed. [2,3,40] The serum testosterone profile shown in Figure 9 correlates very well with the serum PEG-LEU profile shown in Figure 8. The immediate release of PEG-LEU from the film soon after film implantation led to the immediate detection of PEG-LEU in blood ( Figure 8A) and hence a sharp increase in the serum testosterone levels ( Figure 9A) as a result of the initial stimulation of PEG-LEU on the pituitary.…”

Section: Testosterone Suppressionmentioning

confidence: 55%

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Zhuang²,

Zhang³

et al. 2020

Macromolecular Bioscience

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Leuprolide has been widely used in androgen deprivation therapy for the treatment of advanced prostate cancer, but its use is still limited due to its short half‐life. Herein, hydrogen‐bonded layer‐by‐layer films are fabricated from PEGylated leuprolide (PEG‐LEU) and tannic acid (TA). Because of its dynamic nature, the film disintegrates gradually in water and releases PEG‐LEU and TA. The in vitro release profile indicated perfect zero‐order kinetics, which is explained by the unique release mechanism. When implanted subcutaneously in male rats, the films maintain a constant serum drug level. For a 60‐bilayer film, the serum drug level is maintained constant for ≈24 days. No initial burst release is observed, suggesting that the in vivo release also follows zero‐order kinetics. Initially, an increase in the level of serum testosterone is induced by the released drug, followed by testosterone suppression to a constant level below the castrate level, which could be maintained as long as a constant serum drug level is maintained. Since the new drug carriers avoid an initial burst release of the drug and maintain a constant serum drug level and hence a constant serum testosterone level below the castrate level, these carriers are highly promising for androgen deprivation therapy.

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Section: Testosterone Suppressionmentioning

confidence: 55%

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Zhuang²,

Zhang³

et al. 2020

Macromolecular Bioscience

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“…Figure 3 indicates the residual plot of the fold error versus time or observed plasma concentration. It shows the acceptable residual values (fold error <2) at most of the analyzed points, which indicates that the one-compartment model is suitable for the explanation of the plasma concentration profile of tadalafil [35,40].…”

Section: Resultsmentioning

confidence: 99%

Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats

Byeon

Huh

et al. 2019

Pharmaceutics

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Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.

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“…The IVIVC model used in this study was modified from the PK model developed in our previous study of the leuprolide solution treated group and Lucrin depot ® treated group after SC administration [10]. The structure of developed IVIVC model is shown in Figure 2.…”

Section: Development Of Ivivc Modelmentioning

confidence: 99%

“…Elimination of absorbed drugs was interpreted as clearance (CL) and volume of distribution (V d ). k a , CL, and V d were all estimated by one-compartmental analysis from the leuprolide solution-administered group of our previous study [10]. The value of PK parameters was 16.67 h −1 of k a , 514.46 mL/h of CL, 487.40 mL of V d , respectively.…”

Section: Development Of Ivivc Modelmentioning

confidence: 99%

Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

et al. 2020

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This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro–in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration–time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.

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

Cited by 5 publications

References 19 publications

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats

Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

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