摘要:

AbstractA statistical model is set forth that can be taken as a very general description of most data sets that arise from population pharmacokinetic studies. A (nontraditional) method for estimating the parameters of the model—called the NONMEM method in previously published papers—is described. This method involves a linearization of the model. An investigation of the effect of this linearization is reported. This investigation is an empirical one, based on the simulation of data from special cases of the model and the application of a few different estimation methods to these data. From the limited evidence in this investigation it appears that the linearization per se does not significantly adversely affect the estimates.

ISSN:0360-2532    

DOI:10.3109/03602538409015064

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractA simulation study of the one-compartment open pharmacokinetic model has been made. The population pharmacokinetic parameters which characterize the population of drug residues over time are assumed to be stochastic. A general theoretical model framework for parameter estimation via the method of extended least squares is presented. Formulas approximating the required mean and variance time functions are developed and subsequently used in the simulation study. The effects of four different designs in four different animal populations are presented. The simulated data are those of the single observation per animal per time point type. The characterizing population pharmacokinetic parameters have been analyzed for bias and reliability in both a naive and second-order mean model. Recommendations for choosing an appropriate sampling design are included.

ISSN:0360-2532    

DOI:10.3109/03602538409015065

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractIndividual pharmacokinetic parameters can be viewed as independent realizations of a random variable. The probability density function of the variable is assumed to be specified by its first two moments (mean vector and covariance matrix), and these moments then characterize the distribution of the parameters in the population. The following methods are presented for estimation of population characteristics from a set of pharmacokinetic measurements in a sample of subjects:The Global Two-Stage Approach (GTS) uses estimates (and their covariances) of individual parameters obtained after separate fitting of each individual's data.The Iterated Two-Stage Approach (ITS) makes the GTS procedure iterative, using refined bayesian estimates of individual parameters at each step.The Nonlinear Filtering Approach (NLF) also relies on individual parameter estimates produced by using an optimal filter on each subject's data.The three methods give exact results (maximum likelihood estimates), as does NONMEM (the Nonlinear Mixed-Effect Model Approach), when the individual pharmacokinetic model is linear with respect to the parameters and when the distributions of the pharmacokinetic parameters and of the measurement noise in the individual data are both multivariate normal. When the individual pharmacokinetic model is statistically nonlinear (the usual case), the methods differ with respect to: (1) their strategy for handling nonlinearity, (2) their ability to deal with any type of data (experimental and/or routine), and (3) their sensitivity to the amplitude of random effects.With regard to computational aspects, both the computer memory storage requirements and the amount of computation required for the GTS approach are much smaller than for the three other methods.Contrasting considerations as well as results of simulations suggest that GTS, ITS, and, in future, NLF may be valuable alternatives to NONMEM or modifications of it for estimation of population characteristics of pharmacokinetic parameters.

ISSN:0360-2532    

DOI:10.3109/03602538409015066

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractNONMEM, a program package the produces the extended least squares estimates of population parameters for a nonlinear mixed-effect model, has been applied to two data sets from patients routinely receiving phenytoin. A general model for the data is proposed. The models used in previous, standard-method analyses of each data set are compared to the general model using NONMEM. The comparison involves two questions: The first asks whether the parameters estimated previously agree with NONMEM estimates when the original model is used. We find that for fixed-effect parameters they generally do, while for interindividual random-effect parameters the previous methods' estimates appear upward biased relative to NONMEM. Second, the original model per se is compared to the general model by comparing the best fit to each. The general model is clearly superior. NONMEM's ability to distinguish among models, and to precisely estimate their parameters from sparse individual data, is illustrated and verified.

ISSN:0360-2532    

DOI:10.3109/03602538409015067

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractThe generality and flexibility of the computer package NONMEM also confront the user with the difficult task of choosing the model which best describes the data at hand. With two practical examples we show how one may proceed in building the population model for serum concentration measurements. Features of NONMEM are presented which help the user to make the choice among different models.

ISSN:0360-2532    

DOI:10.3109/03602538409015068

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractEthical issues arising from the use of patients in medical research have stimulated pharmacokinetic research in population kinetics, which requires only a few concentration samples of each individual.Using historical maprotiline data, the new approach of population kinetics was investigated and compared to individually estimated kinetics. Two different population kinetic methods were applied. The naive approach, a quick and dirty method, was compared to the nonlinear mixed-effects method, which was applied by the NONMEM package.Based on the results we obtained from actual maprotiline data as well as from simulated data, NONMEM is a reasonable tool for the estimation of population pharmacokinetic parameters. The main advantage of NONMEM over the naive approach lies in the possibility of obtaining standard deviations of random effects related to the variability between subjects.

ISSN:0360-2532    

DOI:10.3109/03602538409015069

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

ISSN:0360-2532    

DOI:10.3109/03602538409015070

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

Abstract1. Both in vivo and in vitro, the dissociation constant K&D50. This was shown for morphine in vivo and for several vasoconstrictors in isolated vascular smooth muscle.3. Values of K obtained from pharmacologic methods can discriminate among receptor subtypes.4. A proper determination of K permits knowledge of the stimulus-response relation, a drug-independent property of the effector system.5. A perturbation of the drug-receptor equilibrium is a way of determining both k1and k2; so far, however, we have been successful only withα-adrenergic vasoconstrictors in which UV light is a suitable stimulus.6. Radiolabeled binding appears to be a precise way of determining K's for agonists and antagonists. However, it does not measure an effect; hence we do not know that such binding sites are true receptors unless we can find a correlation between the values obtained for a series of drugs with this method and those obtained with appropriate pharmacologic methods.

ISSN:0360-2532    

DOI:10.3109/03602538409015071

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractThe body is considered as a system composed of a number of subsystems. The response(s) of a drug is a complicated function of the concentration in the blood plasma, which in turn is some function of the dosage input.The dose-response curve of a drug in a subsystem (e.g., isolated organ) is, over a limited concentration range, a linear function of the logarithm of the concentration. The logarithm of the concentration in the plasma is, again over a limited range, a linear function of time. Time-effect curves in the intact organism may therefore be a linear function of time.In reality, the situation is far more complex, because of nonlinear kinetics, nonlinear kinetics of effects in the subsystems, and adaptation phenomena based on feedback regulation, as is illustrated by examples.It is concluded that one should not only consider the body as a system but also study it as a system; that is, apply the dynamic system approach in pharmacology.

ISSN:0360-2532    

DOI:10.3109/03602538409015072

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor

摘要:

AbstractThis paper has attempted to review some of the possibilities we have today to describe the relationships between the kinetics of a drug and the pharmacodynamic responses. In the future we should place a great deal of effort not only on a detailed evaluation of drug absorption and disposition in the body but also on a much more careful characterization of the dose (concentration)-effect relationships. This should be done in vivo, in order to be able to evaluate the complex character of an observed pharmacological effect, and in a dose range as wide as possible. Although not discussed in the present communication, the possibility of active metabolites must always be considered.

ISSN:0360-2532    

DOI:10.3109/03602538409015073

出版商:Taylor&Francis    

年代:1984

数据来源: Taylor