Biomedical subjects

Donald E Mager

Publications and source records attributed to Donald E Mager.

25 records · Page 2Linked to original sources

PubMed2003

Comparative pharmacokinetics of coumarin anticoagulants L: Physiologic modeling of S-warfarin in rats and pharmacologic target-mediated warfarin disposition in man.

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0 mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80-240 h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1 mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man.

Adipose Tissue↗

PubMed2003

Relative immunosuppressive potency of therapeutic corticosteroids measured by whole blood lymphocyte proliferation.

The in vitro immunosuppressive potency of several therapeutic corticosteroids was investigated using a whole-blood lymphocyte proliferation assay. The selected steroids included beclomethasone dipropionate (BDP), betamethasone (BET), budesonide (BUD), dexamethasone (DEX), flunisolide (FLU), fluticasone propionate (FTP), hydrocortisone (HC), methylprednisolone (MPL), prednisolone (PNL), and triamcinolone acetonide (TAA). The ability of phytohemagglutinin to stimulate lymphocytes in whole blood samples obtained from six drug-free male volunteers was tested against drug concentrations ranging from approximately 0.2 to 2000 nM. Data analysis was conducted employing an inhibitory Hill function and nonlinear regression analysis in ADAPT II. The order of drug concentrations producing 50% inhibition (IC(50)) from highest to lowest was HC > PNL > MPL > BDP > BET > DEX > TAA > FLU > BUD > FTP. These IC(50) values are an inverse measure of drug potency, with FTP representing the most potent corticosteroid examined. A linear correlation was found between the log-transformed 1/IC(50) values and the log of the relative receptor affinity (RRA) values obtained from the literature (r(2) = 0.95). These results extend previous studies to include relatively new corticosteroids and further support the use of RRA values as an indirect measure of relative in vitro immunosuppressive potency.

Adrenal Cortex Hormones↗

PubMed2003

Methods of estimation of IC50 and SC50 parameters for indirect response models from single dose data.

The basic indirect response models are described by several pharmacodynamic parameters of which IC(50) (drug concentration eliciting 50% of the maximum inhibition) and SC(50) (drug concentration eliciting 50% of the maximum stimulation) are not readily derived from the response versus time or response versus concentration plots. We discuss limitations of existing methods of IC(50) and SC(50) estimation from single dose data. A novel approach to such estimations based on the area between the baseline and effect curve is introduced. The effects of pharmacokinetic profile, dose, data variability, and number of data on the parameter estimation are analyzed for the new and one of the previously described methods. Our analysis is based on reconstruction of true IC(50) and SC(50) values from rich and sparse computer-generated data sets modified by two noise levels. Extensions of these methods to two dose data sets are presented. Both methods yielded IC(50) and SC(50) close to the known true values. Depending on the factors mentioned above, these methods exhibited different levels of accuracy.

Dose-Response Relationship, Drug↗

PubMed2003

Diversity of mechanism-based pharmacodynamic models.

Pharmacodynamics is the study of the time course of pharmacological effects of drugs. The field of pharmacodynamic modeling has made many advances, due in part to the relatively recent development of basic and extended mechanism-based models. The purpose of this article is to describe the classic as well as contemporary approaches, with an emphasis on pertinent equations and salient model features. In addition, current methods of integrating various system complexities into these models are discussed. Future pharmacodynamic models will most likely reflect an assembly of the basic components outlined in this review.

Cell Division↗

PubMed2003

Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics.

The integrity of current corticosteroid dose equivalency tables, as assessed by mechanistic models for cell trafficking and cortisol dynamics, was investigated in this study. Single, presumably equivalent, doses of intravenous hydrocortisone, methylprednisolone, dexamethasone, and oral prednisolone were given to 5 white men, according to total body weight, in a 5-way crossover, placebo-controlled study. Pharmacodynamic (PD) response-time profiles for T helper cells, T suppressor cells, neutrophils, and adrenal suppression were evaluated by extended indirect response models. For adrenal suppression, prednisolone appears to be less potent than methylprednisolone or dexamethasone. A good correlation was found between the estimated in vivo EC50 values and relative receptor affinity (equilibrium dissociation constants normalized to dexamethasone). Area under the effect curves of all PD responses was calculated using a linear-trapezoidal method. Although T helper cell trafficking and adrenal suppression achieved significant differences by repeated-measures ANOVA (p = 0.014 and 0.022), post hoc analysis using the Bonferroni method revealed no difference between treatments. Although limited by the use of single doses and a relatively small sample size, this study applies mechanistic models for several biomarkers showing that currently used dosing tables reflect reasonable dose equivalency relationships for four corticosteroids.

Adrenal Cortex Hormones↗

PubMed2002

Quantitative structure-pharmacokinetic/pharmacodynamic relationships of corticosteroids in man.

The purpose of this study was to develop quantitative structure-activity/pharmacokinetic relationships (QSAR/QSPKR) for 11 selected corticosteroids in man. Multiple linear regression analysis with an automatic forward step-wise inclusion algorithm was used to construct QSAR/QSPKR models from molecular and submolecular descriptors that were generated using the SYBYL and KowWin computer programs. The final equations describing steroid relative receptor affinity, systemic clearance, volume of distribution, fraction unbound in plasma, and percent of oral absorption, all showed significant correlations (R(2) range 0.841 to 0.977). These relationships were crossvalidated using the leave-one-out method, and appeared to have good predictive performance (Q(2) range 0.715 to 0.912). In addition, a general method for integrating QSAR/QSPKR data to predict the time course of pharmacologic effects is presented. This approach, termed quantitative structure-pharmacodynamic relationships modeling, was successfully applied to predict the rapid cortisol suppressive effects of triamcinolone acetonide after a 2-mg intravenous bolus dose in healthy volunteers.

Adrenal Cortex Hormones↗

PubMed2002

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

PURPOSE: An integrated receptor-based pharmacokinetic/pharmacodynamic (PK/PD) model of interferon-beta la (IFN-beta la) 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 I 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 (Smax = 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-beta 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.

Female↗