Journal of Pharmacokinetics and Biopharmaceutics最新文献

Six mathematical functions to describe the chronobiology of cortisol concentrations were assessed. Mean data from a dose-proportionality study of inhaled fluticasone propionate were fitted with an indirect response model using various biorhythmic functions (single cosine, dual ramps, dual zero-order, dual cosines, and Fourier series with 2 and n-harmonics) for production rate. Data with known parameters and random variation were also generated and fitted using the ADAPT II program. Fitted parameters, model estimation criteria, and runs tests were compared. Models with preassigned functions: the dual ramps, the dual zero-order and the dual cosines provide maximum and minimum times for cortisol release rate, were suitable for describing asymmetric circadian patterns and yielding IC50 values. Fourier analysis differs from the other methods in that it uses the placebo data to recover equations for cortisol secretion rate rather than by postulation. Nonlinear regression for Fourier analysis, instead of the L2-norm method, was useful to characterize the baseline cortisol data but was restricted to a maximum of two harmonics. Apart from the single cosine function, which predicts symmetrical cortisol concentrations, all methods were satisfactory in describing the baseline and suppressed cortisol concentrations. On the other hand, Fourier series with L2-norm produced the best unbiased estimate for baseline patterns. The Fourier method is flexible, accurate, and can be extended to other drug-induced changes in normal periodic rhythms.

The rate and extent of binding of methazolamide to human erythrocytes was studied in vitro. All experiments were carried out at physiological temperature (37 C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 +/- 0.00022 microM-1) nM1 (636 +/- 5.23 microM), Ka2(0.46 +/- 0.0083 microM-1), and nM2(80.9 +/- 0.389 microM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 +/- 0.000618 cm/min), and binding rate constants k-1(0.254 +/- 0.0213 min-1), k1 (0.0022 +/- 0.00020 ml/microgram-min), k-2(1.59 +/- 0.0358 min-1), and k2(3.1 +/- 0.035 ml/microgram-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.

Modeling of nonlinear pharmacodynamic (PD) relationships necessitates the utilization of a weighting function in order to compensate for the heteroscedasticity. The structure of the variance was studied for concentration-effect data generated in an in vitro 96-well plate cell growth inhibition assay, where data are numerous (480 data points per experiment) and replication is easy. From the five candidate models that were considered, the power function S2Y = phi 2Y phi 3, where Y is the sample mean and S2Y is the sample variance, was shown to be the most appropriate to describe the nonuniformity of the variance along the range of measured effect for 253 sets of (Y; S2Y) data. The Hill model was fit to the concentration-effect data with weighted nonlinear regression, where the weights were equal to the reciprocal of the predicted variance. The examination of the distribution of the 253 sets of parameters of the PD model showed that IC50 was lognormally distributed whereas the distribution of gamma was normal. The characterization of the appropriate variance function and concentration-effect function in a simple in vitro experimental setting with a large number of experiments, with each experiment including a large number of data points, will be useful for guiding similar in vitro concentration-effect studies where data are plentiful and for guiding PD modeling in complex clinical settings in which extensive data for model characterization is impossible to obtain.

Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m2) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration-time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC0-t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC0-infinity, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 micrograms * hr/ml; p = 0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.

This study aimed to evaluate the relative importance of diffusion-limited vs. perfusion-limited mechanisms in compartmental models of blood-tissue inert gas exchange in the brain. Nitrous oxide concentrations in arterial and brain efferent blood were determined using gas chromatographic analysis during and after 15 min of nitrous oxide inhalation, at separate low and high steady states of cerebral blood flow (CBF) in five sheep under halothane anesthesia. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of the brain were estimated by simultaneous fitting of the models to the mean observed brain effluent nitrous oxide concentration for both blood flow states. Perfusion-limited models returned precise, credible estimates of apparent brain volume but fit the low CBF data poorly. Diffusion-limited models provided better overall fit of the data, which was best described by exchange of nitrous oxide between a perfusion-limited brain compartment and an unperfused compartment. In individual animals, during the low CBF state, nitrous oxide kinetics displayed either fast, perfusion-limited behavior or slow, diffusion-limited behavior. This variability was exemplified in the different parameter estimates of the diffusion limited models fitted to the individual animal data sets. Results suggest that a diffusion limitation contributes to cerebral nitrous oxide kinetics.

Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by i.v. injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3-14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1-2 hr, reached a maximum at 5-6 hr, and declined to the baseline at 12-14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1-2 hr. The low-dose group had 50-60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50-60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.

An empirical equation was recently proposed and used to characterize inhibitory drug effects on production of an endogenous substance. The limitations of this empirical equation are described utilizing mathematical equations and simulations based on the exact differential equation for Indirect Response Model I. The latter is preferable for fitting data using indirect response models.

The expectation of the determinant of the inverse of the population Fisher information matrix is proposed as a criterion to evaluate and optimize designs for the estimation of population pharmacokinetic (PK) parameters. Given a PK model, a measurement error model, a parametric distribution of the parameters and a prior distribution representing the belief about the hyperparameters to be estimated, the EID criterion is minimized in order to find the optimal population design. In this approach, a group is defined as a number of subjects to whom the same sampling schedule (i.e., the number of samples and their timing) is applied. The constraints, which are defined a priori, are the number of groups, the size of each group and the number of samples per subject in each group. The goal of the optimization is to determine the optimal sampling times in each group. This criterion is applied to a one-compartment open model with first-order absorption. The error model is either homoscedastic or heteroscedastic with constant coefficient of variation. Individual parameters are assumed to arise from a lognormal distribution with mean vector M and covariance matrix C. Uncertainties about the M and C are accounted for by a prior distribution which is normal for M and Wishart for C. Sampling times are optimized by using a stochastic gradient algorithm. Influence of the number of different sampling schemes, the number of subjects per sampling schedule, the number of samples per subject in each sampling scheme, the uncertainties on M and C and the assumption about the error model and the dose have been investigated.

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

A numerical calculation method for dispersion models was developed to analyze nonlinear and nonsteady hepatic elimination of substances. The finite difference method (FDM), a standard numerical calculation technique, was utilized to solve nonlinear partial differential equations of the dispersion model. Using this method, flexible application of the dispersion model becomes possible, because (i) nonlinear kinetics can be incorporated anywhere, (ii) the input function can be altered arbitrarily, and (iii) the number of compartments can be increased as needed. This method was implemented in a multipurpose nonlinear least-squares fitting computer program, Napp (Numeric Analysis Program for Pharmacokinetics). We simulated dilution curves for several nonlinear two-compartment hepatic models in which the saturable process is assumed in transport or metabolism, and investigated whether they could definitely be discriminated from each other. Preliminary analysis of the rat liver perfusion data of a cyclic pentapeptide, BQ-123, was performed by this method to demonstrate its applicability.