Ocular pharmacokinetic/pharmacodynamic modeling for multiple anti-glaucoma drugs

We have constructed a new ocular pharmacokinetic pharmacodynamic (PK/PD) model for anti-glaucoma drugs to describe ocular hypotensive effects on intraocular pressure (IOP) after instillation of a combination of an alpha(1)-adrenergic antagonist, bunazosin, and a beta-adrenergic antagonist, timolol, into rabbits. This model was constructed by the combination of two ocular PK/PD models for bunazosin and timolol by including aqueous humor dynamics based on both action mechanisms. We also verified the reliability of this model by confirming the drug concentrations in aqueous humor and ocular hypotensive effects after instillation of the drug combination. The aqueous humor concentrations of timolol and bunazosin were determined by an HPLC, and ocular hypotensive effect-time profiles were measured using a telemetry system, which was able to record automatically detailed effects. The combined model could simulate the aqueous humor concentrations of both drugs and the additive IOP-lowering effect after instillation of the combination using the MULTI (RUNGE) program and PK/PD parameters which were obtained from ocular hypotensive effects after instillation of bunazosin alone or timolol alone. The theoretical concentration curves of both drugs in the aqueous humor and the theoretical ocular hypotensive effect curves almost agreed with both the observed concentrations and ocular hypotensive effects after instillation of the drug combination. These results indicate the reliability and usefulness of PK/PD modeling considering aqueous humor dynamics to predict IOP in multidrug therapy. This is the first study to develop a PK/PD model for multidrug therapy for the eye.     

Development of a model for integrated pharmacokinetic and pharmacodynamic studies of intravenous anaesthetic agents: Application to minaxolone

Summary This study reports an approach to the investigation of new intravenous anaesthetic agents. Minaxolone (0.5%) was administered to healthy young adult volunteers in three different phases of study: (i) Subanaesthetic constant-rate infusion of 0.01 mg·kg^–1min^–1 for 120 min; (ii) Subanaesthetic and anaesthetic infusion regimens of 0.05 mg·kg^–1 min^–1 for 60 min, followed immediately by 0.020 mg·kg^–1min^–1 for 60 min; approximately four weeks later the same subjects received infusions of 0.01 mg·kg^–1min^–1 and 0.015 mg·kg^–1min^–1 respectively for the same period of time; (iii) Bolus injections of 10 mg and 40 mg over 1 min, at 2 h apart. Similar pharmacokinetic parameters were derived from all three different regimens, most notably characterised by high total body clearance (1.6 to 3.2l·min^–1), correlating with rapid lucid clinical recovery of CNS function. Renal clearance was less than 0.5% of total body clearance, which was consistently 2 to 3 times the clearance of indocyanine green. Terminal half-life was short.The subanaesthetic infusion regimen of minaxolone produced a sleep-like state from which subjects were rousable, obeyed commands readily and maintained verbal contact with investigators, while remaining amnesic throughout. This occurred at blood minaxolone concentration of 0.14 to 0.15 mg·l^–1. In the second stage, general anaesthesia was induced at a mean blood minaxolone concentration of 0.24 mg·l^–1 (SD 0.11). Intravenous bolus injections of 40 mg minaxolone invariably induced anaesthesia with mean blood concentrations of 0.49 mg·l^–1 (SD 0.29) 2 min postinjection. Onset of anaesthesia was very rapid, mean 55 s (SD 10), with a consistent duration of anaesthesia (mean 23 min, SD 3). Recovery was very rapid and lucid, without any tendency to lapse back into sleep again.Generally, the incidence of adverse effects was greatest with anaesthetic bolus doses and least with subanaesthetic infusions. Whilst only mild excitatory movements were observed in 60% of subjects who received the subanaesthetic infusion, these increased in frequency and intensity with the anaesthetic infusions and occurred with the greatest severity in all subjects who received the 40 mg bolus injection. Tachycardia invariably was noted in all phases of study. A remarkably high incidence of respiratory upsets, in the form of tachypnoea, hyperventilation, apnoea, hiccoughs and laryngospasm, was observed with the 40 mg bolus dosage. Minaxolone, therefore, whilst possessing pharmacokinetic properties desirable of an IV anaesthetic agent, had disturbing clinical effects which may limit its clinical use. Using this approach, studies in only 15 volunteer subjects were successful in describing the pharmacokinetics, blood concentration-response relationships as well as the incidence and nature of side effects. On the basis of these data, it was possible to determine that the new drug, minaxolone, did not show sufficient promise to warrant further development. This methodology would seem to provide a useful model in the investigation of new intravenous anaesthetics to optimise patient safety and development costs.     

A rat pharmacokinetic/pharmacodynamic model for assessment of lipopolysaccharide-induced tumor necrosis factor-alpha production

INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) participates in many inflammatory processes. TNFalpha modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFalpha synthesis or release. METHODS: Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFalpha were determined. The areas under the concentration-time curves (AUC(drug) and AUC(TNFalpha)) were calculated. The overall percentage of inhibition on TNFalpha release in vivo was calculated by comparing AUC(TNFalpha) of the test article treated group against that for the vehicle control group. RESULTS: The dosing vehicles tested in this study did not increase plasma TNFalpha level. At IV dose of up to 100 microg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFalpha converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFalpha plasma levels in vivo. DISCUSSION: A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFalpha synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.     

脑微透析技术及其在脑内药动/药效学研究中的应用

<正>脑微透析技术是从神经科学基础上发展起来的,是一种实现连续在线监测活体脑内完整细胞外液物质(包括内源性和外源性物质)动态变化的新型     

An age-dependent physiologically based pharmacokinetic/pharmacodynamic model for the organophosphorus insecticide chlorpyrifos in the preweanling rat.

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance are CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (B-est) and PON-1 (A-esterase) detoxification of CPF-oxon to TCP. In the current study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue B-est levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue cholinesterase (ChE) levels. In addition, age-dependent changes in brain, liver, and fat volumes and brain blood flow were obtained from the literature and used in the simulations. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent nonlinear increase in CPF-oxon concentration may potentially result from both the depletion of nontarget B-est and a lower PON-1 metabolic capacity in younger animals. The PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics, and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.     

An analytical pharmacodynamic model for nondepolarizing neuromuscular blocking agents

A pharmacodynamic model for nondepolarizing neuromuscular blocking agents (NMBA) is developed and tested with different sets of data (NMBA plasma concentration and time evolution of muscular paralysis). This model takes into account the binding of NMBA to the cholinergic motor endplate receptors and thus permits estimation of the apparent equilibrium constant of the NMBA-receptor exchange. The parameters defining the relationship between relative postsynaptic receptor occupation and muscular paralysis can also be determined. The simulated muscular paralysis time curves, calculated for various modes of NMBA administration (loading injection and multiple injections or continuous infusion) are comparable to those observed clinically. As compared to previous NMBA pharmacodynamic models, the model presented in this study utilizes and describes all the main steps between changes in the plasma NMBA concentration and the observed response: pharmacokinetics, ligand-receptor exchanges, and receptor occupation-effect relationship. This model illustrates a general methodology for the study of pharmacokinetic and pharmacodynamic problems.     

An analytical pharmacodynamic model for nondepolarizing neuromuscular blocking agents

A pharmacodynamic model for nondepolarizing neuromuscular blocking agents (NMBA) is developed and tested with different sets of data (NMBA plasma concentration and time evolution of muscular paralysis). This model takes into account the binding of NMBA to the cholinergic motor endplate receptors and thus permits estimation of the apparent equilibrium constant of the NMBA-receptor exchange. The parameters defining the relationship between relative postsynaptic receptor occupation and muscular paralysis can also be determined. The simulated muscular paralysis time curves, calculated for various modes of NMBA administration (loading injection and multiple injections or continuous infusion) are comparable to those observed clinically. As compared to previous NMBA pharmacodynamic models, the model presented in this study utilizes and describes all the main steps between changes in the plasma NMBA concentration and the observed response: pharmacokinetics, ligand-receptor exchanges, and receptor occupation-effect relationship. This model illustrates a general methodology for the study of pharmacokinetic and pharmacodynamic problems.     

Development of an intravenous microdialysis method for pharmacokinetic investigations in humans

INTRODUCTION: Limited blood volume is a major problem in pharmacokinetic investigations in specific populations, e.g. children. Intravenous microdialysis might help to obtain improved data sets as it is already successfully done in small animals. Since quantification of drugs is crucial in microdialysis, we developed an in vitro method to produce a workable intravenous microdialysis for human use. METHODS: A specifically designed microdialysis cell consisting of glass was heated to 37 degrees C. The cell was filled with Ringer's solution, plasma or whole blood. A microdialysis probe was inserted into the cell and perfused with Ringer's solution with addition of 4% dextran. The beta-receptor blocker sotalol served as a test drug. The stepwise in vitro evaluation process addressed issues of loss of dialysate, calibration by retrodialysis and relative recovery. These conditions were then applied in an in vivo pilot study to one single healthy volunteer after written informed consent. RESULTS: To address loss of perfusion fluid 4% of dextran was added and high and constant amounts of dialysate were achieved. To account for changes in the relative recovery a continuous use of retrodialysis by the calibrator atenolol was introduced. The recovery of atenolol was comparable to sotalol. The pharmacokinetic analysis revealed that sotalol concentrations from microdialysates were not different from conventional plasma samples (100+/-11%, n=33) resulting in subsequent comparable pharmacokinetic parameters. DISCUSSION: This stepwise approach using an in vitro device enabled us to demonstrate the determination of pharmacokinetic parameters of sotalol. The most important evaluation step is represented by the continuous use of retrodialysis by the calibrator atenolol because it can account for changes in the relative recovery of the drug. This approach should be a starting point to simplify pharmacokinetic studies in special populations, e.g. in small children, to improve drug treatment.     

微透析技术在抗菌药物药动学和药效学中的应用

微透析技术是一项新兴的体内药物分析技术。通过微透析技术与药动学和药效学模型结合,实现对组织或细胞外游离态药物浓度及其相应药理效应的同时研究,不仅有利于进一步明确药物的剂量-效应关系,制定临床最佳给药方案,而且也为个体化给药提供了科学依据。本文综合近年文献,对微透析技术的基本原理以及在抗菌药物药动学和药效学研究中的应用作一综述。     

Physiological pharmacokinetic and pharmacodynamic model of physostigmine in the rat.

A physiological model for physostigmine disposition was developed in the rat which incorporated anatomical, physiological, and biochemical parameters, i.e. tissue volume, plasma flow rates, drug metabolism, and tissue-to-plasma partition coefficients. Predicted concentrations of physostigmine in different tissue compartments were consistent with the experimental observations in the rat following an iv dose. Part of this study also compared the time course changes in measured effect, as percentage change in cholinesterase activity in brain, and related these changes to the plasma or brain drug level in either a combined pharmacokinetic-pharmacodynamic (plasma physostigmine-effect relationship) or a dynamic model (brain physostigmine-effect relationship). Fitting the time course of the effect in a pharmacokinetic-pharmacodynamic model required an effect compartment with the equilibration rate constant between it and the plasma compartment. Both models help to understand whether the cholinesterase activity is homogeneous or heterogenous in the brain.     

肠促胰岛素相关药物的药代动力学／药效学模型研究进展

肠促胰岛素是一类在食物刺激下由肠道L细胞分泌并能促使胰岛素分泌的激素,其主要包括胰高血糖素样肽－1（ GLP－1）受体激动剂类似物和二肽基肽酶－4（DPP－4）抑制剂。药代动力学／药效学（PK／PD）结合模型可以为肠促胰岛素相关药物的治疗和临床研究提供有力的工具,同时,基于机制的模型可以更好地预测给药后的生理学特点和不同给药方案的治疗结果,有利于该类药物新药研发及给药方案的调整。本文主要针对 GLP －1受体激动剂类似物和DPP－4抑制剂代表药物基于其作用机制的PK／PD模型进行综述。     

Methodology for pharmacokinetic/pharmacodynamic data analysis

This review will highlight the role of exploratory data analysis and nonlinear regression software in pharmacokinetic–pharmacodynamic (PK/PD) data analysis. Kinetic and dynamic modelling situations typical to the pharmacokineticist in the drug industry will be addressed, and two case studies, including single-dose intravenous bolus plasma data and multiple-dose response-time data will be analysed. Approaches to assessing the suitability of model fit to the observed data will be discussed, and a summary of the key features of available commercial PK software will be given. Specific emphasis will be placed on the application of WinNonlin.     

Predictive population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor

The objectives of these analyses were to (1) develop a population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor (CS-706) using data from primarily Caucasian subjects, (2) predict responses in subpopulations of interest (including Japanese subjects), and (3) correlate pharmacodynamic parameters to safety outcomes. The model was developed using data from 130 healthy adults following single or multiple doses of CS-706. Serial plasma concentrations of CS-706 and ex vivo whole-blood cyclooxygenase-1 (COX-1) and COX-2 activity were determined up to 72 hours postdose. An E(max) model described relationships between CS-706 plasma concentrations and COX-1 and COX-2 inhibition. CS-706 potency (EC(50)) was 397 ng/mL for COX-1 and 20 ng/mL for COX-2. None of the tested covariates influenced the pharmacodynamics of CS-706. Japanese subjects are expected to show a slightly reduced response to CS-706, consistent with lower exposure following the same dose given to Caucasian subjects. Predictive pharmacokinetic/pharmacodynamic modeling for COX-1 and COX-2 inhibition indicates a 20-fold potency ratio that is expected to be similar in Japanese and Caucasians. There was good correlation between COX-1 inhibition and the incidence of 7-day gastroduodenal mucosal injury. A dose of less than 25 mg bid could be adequate to inhibit COX-2 activity with a low risk of gastrointestinal mucosal injury.     

Validation of a population pharmacokinetic/pharmacodynamic model for 5 alpha-reductase inhibitors.

A population pharmacokinetic/dynamic model describing the conversion of testosterone to dihydrotestosterone (DHT) by 5alpha-reductases and the irreversible inhibition of 5alpha-reductase(s) by finasteride and dutasteride was validated. The model had been developed using data from a single dose study in healthy volunteers and was validated against data from a 28-day repeat dose study in patients with benign prostatic hyperplasia. Validation was carried out by comparing results of Monte Carlo simulations to the observed data, fitting the model to the repeat dose data and comparing with previously derived parameter values, and examining individual predictions of the model for the individuals in the repeat dose study for any bias. Simulations closely predicted the outcome of the repeat dose study, estimated parameters of the pharmacodynamic modelling were generally close to within 88 to 116% of those from the original model and the individual predictions did not indicate any bias. Thus the model derived from single dose data from healthy volunteers was considered to be valid for the prediction of DHT levels in the patient population after repeated dosing of dutasteride and finasteride.     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

Population pharmacokinetic and pharmacodynamic model of norvancomycin

去甲万古霉素群体药代动力学与药效学研究@张菁$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China@张婴元$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China@施耀国$Institute of Antibiotic     

A pharmacodynamic model for cell-cycle-specific chemotherapeutic agents

A pharmacodynamic model is proposed and equations are developed for the quantitative analysis of dose-time-cell-survival curves produced by the administration of cell-cycle-specific chemo-therapeutic agents. The essential feature of the model is an irreversible, bimolecular mechanism of drug-receptor interaction which serves as the interface between the pharmacokinetics of the drug and the cell-cycle-cell-proliferation kinetics of the normal and neoplastic cells. A preliminary cell system which allows adequate characterization of the experimental data is a two-compartment model where cells are assumed to exist in their proliferative and nonproliferative phases. The chemotherapeutic model was used to analyze dose-time-cell-survival curves found in the literature for the effects of vincristine, vinblastine, arabinosylcytosine, and cyclophosphamide on lymphoma and hematopoietic cells in the mouse femur. Similarity in the values of the cell-kill constants for these drugs on the two cell types indicates that, in the cell systems studied, the proliferative state of the cells is the primary in vivodeterminant of selective chemotherapy.Presented, in part, at the A.Ph.A. Academy of Pharmaceutical Sciences Symposium on Pharmacokinetics in Disease, Houston, Texas, April 1972, and at the Fogarty International Conference on Pharmacology and Pharmacokinetics, Washington, D.C., November 1972.     

Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in humans

Purpose. An integrated receptor-based pharmacokinetic/pharmaco- dynamic (PK/PD) model of interferon- 1a (IFN- 1a) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans. Methods. Data were extracted from the literature by digitalization. Single-dose (3 IV doses and 1 SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs). Results. The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (S_max = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels. Conclusions. The present integrated PK/PD model for IFN- 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.     

A genetic algorithm based global search strategy for population pharmacokinetic/pharmacodynamic model selection

The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection.