Abstract
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.
Highlights
Peptide and protein drugs have been increasingly important in the pharmaceutical industry, because of the advances in biotechnology and genetic engineering, and because of better understanding of their role in physiology and pathology [1]
Peptide drugs could have many valuable applications in clinical medicine, but so far applications of chemically synthesized peptides have been severely limited by their low systemic stability, high clearance, poor membrane permeability, and high costs of manufacturing [4]
The drug was already 10–20% released at the start of the release test, and a rapid release pattern was observed with a steep curve up to 4 or 5 days after the initial release
Summary
Peptide and protein drugs have been increasingly important in the pharmaceutical industry, because of the advances in biotechnology and genetic engineering, and because of better understanding of their role in physiology and pathology [1]. Peptide drugs are defined as molecules containing fewer than 50 amino acids and have many advantages [2]. They bind to their specific targets, resulting in high potencies of action and relatively few off-target side effects. Peptide drugs are fine-tuned to interact with biological targets, evolving into potent endogenous hormones, growth factors, neurotransmitters, signaling molecules, and immunologic and defense agents [3]. Peptide drugs could have many valuable applications in clinical medicine, but so far applications of chemically synthesized peptides have been severely limited by their low systemic stability, high clearance, poor membrane permeability, and high costs of manufacturing [4].
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