ABSTRACT
Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.
Subject(s)
Cardiovascular Diseases/chemically induced , Cardiovascular System/drug effects , Drug-Related Side Effects and Adverse Reactions/etiology , Pharmaceutical Preparations/administration & dosage , Animals , Blood Pressure/drug effects , Dogs , Drug Discovery/methods , Drug Evaluation, Preclinical , Guinea Pigs , Heart Rate/drug effects , Humans , Macaca mulatta , Rabbits , RatsABSTRACT
Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h. The main route of elimination was via the urine in dogs and female rats, but via the faeces in male rats and mice of both sexes. Zibotentan was moderately bound to plasma proteins of all species examined (55-95%), and widely distributed throughout all tissues with the highest concentrations seen in the organs of excretion. Zibotentan was moderately metabolised. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine.
Subject(s)
Endothelin A Receptor Antagonists , Pyrrolidines/metabolism , Pyrrolidines/pharmacokinetics , Administration, Oral , Animals , Biotransformation , Blood Proteins/metabolism , Chromatography, High Pressure Liquid , Dogs , Female , Male , Mice , Protein Binding , Pyrrolidines/administration & dosage , Pyrrolidines/blood , Radioactivity , Rats , Receptor, Endothelin A/metabolism , Tissue DistributionABSTRACT
OBJECTIVE: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. METHODS: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. RESULTS: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. CONCLUSIONS: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Prostatic Neoplasms/drug therapy , Pyrrolidines/pharmacokinetics , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Asian People , Body Weight , Dose-Response Relationship, Drug , Endothelin A Receptor Antagonists , Half-Life , Humans , Japan , Male , Middle Aged , Prostatic Neoplasms/pathology , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Tissue Distribution , White PeopleABSTRACT
The retinal pigment epithelium (RPE) plays a major role in the development of proliferative vitreoretinopathy (PVR). In particular, RPE cells are implicated in generating the contraction forces seen. The present study was undertaken to investigate whether human RPE binds a lectin from the common edible mushroom, Agaricus bisporus, and to evaluate the effect of any binding on RPE-mediated matrix contraction in an in vitro model of PVR. Fluorescein isothiocyanate (FITC)-labelled Agaricus bisporus lectin (ABL) was used to study binding of lectin to normal retina, PVR scar tissue specimens and cultured human RPE. The effect of a 3-day exposure of ABL on human RPE-mediated contraction was evaluated using 2- and 3D RPE-populated collagen matrices. Effect of ABL on cell adhesion was measured using a collagen type I adhesion assay and determining the relative cellular attachment using absorbance readings. The normal RPE monolayer did not stain with FITC-ABL while PVR scar tissue stained intensely. Staining of in vitro RPE was characteristic but time-dependent. ABL caused a dose-dependent inhibition of RPE-mediated contraction of both 2D (one-way ANOVA, F = 7.94, p < 0.008) and 3D collagen matrices (one-way ANOVA, F = 164.955, p < 0.001). Pre-incubation of ABL with RPE in the 2D model caused a dramatic arrest of contraction (one-way ANOVA, F = 20.1, p < 0.001) that was due to a dose-dependent inhibition of adhesion (one-way ANOVA, F = 15.603, p < 0.001). Recovery of contraction was partially reversible on removal of ABL and was dependent on initial concentration of the lectin. ABL inhibits contraction and adhesion of human RPE cells in vitro without apparent cytotoxicity. It therefore deserves consideration as a potential therapeutic agent in the prevention and treatment of PVR and other non-ocular anomalous wound-healing processes.
