Journal of Pharmacokinetics and Biopharmaceutics最新文献

{"title":"Meeting announcements","authors":"R. Guy, R. Wester","doi":"10.1007/BF01059093","DOIUrl":"https://doi.org/10.1007/BF01059093","url":null,"abstract":"","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"71 1","pages":"139-140"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80140903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitivity analysis of pharmacokinetic and pharmacodynamic systems: I. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models.","authors":"I A Nestorov","doi":"10.1023/a:1020926525495","DOIUrl":"10.1023/a:1020926525495","url":null,"abstract":"<p><p>Based on a frequency response approach to the sensitivity analysis of pharmacokinetic models, the concept of structural sensitivity is introduced. The core of this concept is the factorization of the system sensitivity into two multipliers. The first one, called structural sensitivity index, has an analytical form, which depends solely on the structure and connectivity of the system and does not depend on the drug administered or the factor perturbed. The second multiplier, the parameter sensitivity index, depends on the drug properties, the tissue of interest and the parameter perturbed, but is largely independent of the structure of the system. The structural and parametric sensitivity indices can be evaluated and analyzed separately. The most important feature of the proposed approach is that the conclusions drawn from the analysis of the structural sensitivity index are valid across all mammalian species, as the latter share a common anatomical and physiological structure. The concept of structural sensitivity is illustrated on the commonly used structure of the whole body physiologically based pharmacokinetic models by showing that the factorization of the sensitivity carried out arises naturally from the mechanism of the distribution of perturbations throughout the organism. The concept of structural sensitivity has interesting practical implications. It enables the formal proof of relationships and facts that have been observed previously. Moreover, the conclusions drawn introduce in fact a ranking of the tissues or subsystems with respect to their impact on the model outputs. From this ranking, direct recommendations regarding the design of experiments for whole-body physiologically based pharmacokinetic models are derived.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"413 1","pages":"577-96"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86840389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based pharmacokinetics of cyclosporine A: reevaluation of dose-nonlinear kinetics in rats.","authors":"C Tanaka, R Kawai, M Rowland","doi":"10.1023/a:1020978509566","DOIUrl":"10.1023/a:1020978509566","url":null,"abstract":"<p><p>The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide i.v. dose range (1.2-30 mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CLb). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vuss) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis-Menten kinetics, Km 0.60 microgram/ml. In model-based simulations, both volume of distribution at steady state (Vss,b) and CLb varied in a similar manner with dose, such that terminal t1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood-brain barrier.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"16 1","pages":"597-623"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81337673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron.","authors":"E H Cox, C Veyrat-Follet, S L Beal, E Fuseau, S Kenkare, L B Sheiner","doi":"10.1023/a:1020930626404","DOIUrl":"10.1023/a:1020930626404","url":null,"abstract":"<p><p>This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard function for emesis that is increased by ipecac administration and decreased by ondansetron concentration. The model is fit using an approximate maximum likelihood method. The data consist of the time free of emeses and, for those individuals with emetic episodes, the time(s) of the episode(s). Model evaluation is accomplished using residual plots adapted to time-to-event data and a \"posterior predictive check\" wherein observed data statistics are compared to those obtained from data simulated from the fitted model. The ondansetron concentration required to obtain a 50% reduction in the hazard of emesis is estimated to be 1.4 +/- 0.2 ng/ml, and the rate constant for elimination of ipecac-induced hazard is 1.5 +/- 0.2 hr-1.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"59 1","pages":"625-44"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89562368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling interactions between adrenal suppression and T-helper lymphocyte trafficking during multiple dosing of methylprednisolone.","authors":"F S Chow, A Sharma, W J Jusko","doi":"10.1023/a:1020974408657","DOIUrl":"10.1023/a:1020974408657","url":null,"abstract":"<p><p>A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"21 1","pages":"559-75"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85301839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Basic pharmacodynamic models for agents that alter production of natural cells.","authors":"W Krzyzanski, R Ramakrishnan, W J Jusko","doi":"10.1023/a:1023249813106","DOIUrl":"10.1023/a:1023249813106","url":null,"abstract":"<p><p>Basic indirect pharmacodynamic models for agents which alter the generation of natural cells based on a life-span concept are introduced. It is assumed that cells (R) are produced at a constant rate (kin), survive for a specific duration TR, and then are lost. The rate of cell loss must equal the production rate but is delayed by TR. A therapeutic agent can stimulate or inhibit the production rate according to the Hill function: 1 +/- H(C(t)) where H(C(t)) contains capacity (Smax) and sensitivity (SC50) constants and C(t) is a pharmacokinetic function. Thus an operative model is [equation: see text] with the baseline condition R0 = kin.TR. One- and two-compartment catenary cell models were examined by simulation to describe the role of pharmacokinetics and cell properties. The area under the effect curve (AUCE) was derived. The models were applied to literature data to describe the stimulatory effects of single doses of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) on neutrophils, thrombopoietin (TPO) on platelets, and erythropoietin (EPO) on reticulocytes in blood. The models described experimental data adequately and provided cell life-spans and SC50 values. The proposed cell production/loss models can be readily used to analyze the pharmacodynamics of agents which alter cell production yielding realistic physiological parameters.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"27 5","pages":"467-89"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21785682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indirect-response modeling of desmopressin at different levels of hydration.","authors":"T Callréus, J Odeberg, S Lundin, P Höglund","doi":"10.1023/a:1023238514015","DOIUrl":"10.1023/a:1023238514015","url":null,"abstract":"<p><p>The objective of the present study was to investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of desmopressin in healthy male subjects at different levels of overhydration. Also, we examined if an indirect-response model could be related to renal physiology and the pharmacological action of desmopressin. Eight healthy male subjects participated in this open, randomized crossover study with three periods. Each subject was orally water loaded (0 to 20 ml.kg-1 body weight) on 3 study days in order to achieve three different levels of hydration. After the initial water load, urine was voided every 15 min and the volumes were measured. To ensure continuous overhydration the subjects replaced their fluid loss with drinking-water. When a steady-state diuresis was achieved after approximately 2 hr, 0.396 microgram of desmopressin was administered intravenously as a bolus injection. Blood was sampled and urine was collected at intervals throughout the study day (10 hr). An indirect-response model, where desmopressin was assumed to inhibit the elimination of response, was fit to the urine osmolarity data. There were no statistically significant effects of different levels of hydration, as expressed by urine flow rate at baseline, on the estimates of the PK and PD model parameters. The calculated terminal half-lives of elimination (t1/2 beta) ranged between 2.76 and 8.37 hr with an overall mean of 4.36 hr. The overall means of plasma clearance and the volumes of distribution of the central compartment (Vc) and at steady state (Vss) were estimated to be 1.34 (SD 0.35) ml.min-1.kg-1, 151 (SD28) ml.kg-1, and 386 (SD 63) ml.kg-1, respectively. High urine flow rate, indicating overhydration, produced a diluted urine and thus a low osmolarity at baseline (R0). The effect of the urine flow rate on the urine osmolarity at baseline was highly significant (p < 0.0001). The mean values for IC50 and the sigmodicity factor (gamma) were 3.7 (SD 1.2) pg ml-1 and 13.0 (SD 3.5), respectively. In most cases when there was a high urine flow rate at baseline, the model and the estimated PD parameters could be related to the pharmacological action of desmopressin and renal physiology. Thus, the indirect-response model used in this study offers a mechanistic approach of modeling the effect of desmopressin in overhydrated subjects.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"27 5","pages":"513-29"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21785684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-drug pharmacodynamic interaction detection by a nonparametric population approach. Influence of design and of interindividual variability.","authors":"Y Merlé, A Mallet, E Schmautz","doi":"10.1023/a:1023290530853","DOIUrl":"10.1023/a:1023290530853","url":null,"abstract":"<p><p>Population approaches are appealing methods for detecting then assessing drug-drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug-drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"27 5","pages":"531-54"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21785685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assuming peripheral elimination: its impact on the estimation of pharmacokinetic parameters of muscle relaxants.","authors":"J Laurin, F Nekka, F Donati, F Varin","doi":"10.1023/a:1023286329945","DOIUrl":"10.1023/a:1023286329945","url":null,"abstract":"<p><p>For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10) and peripheral compartments (k20). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss) are also mostly significant when k20 is smaller than k10. Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20, the rate of transfer from the central compartment (k12) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"27 5","pages":"491-512"},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21785683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability of the model-independent AUC: the one sample per individual case.","authors":"W Jawień","doi":"10.1023/a:1020921323001","DOIUrl":"10.1023/a:1020921323001","url":null,"abstract":"<p><p>A theory is developed for estimation of a population value of AUC along with its standard deviation, in the case, when only one concentration-time (C-t) sample is available for each individual. This theory is based on model-independent pharmacokinetics. Integration methods are classified due to their applicability to the presented approach. The main goal of this work is to establish a statistical hypothesis-testing procedure which would make single C-t samples usable for bioequivalence studies. An application of the theory to a number of integration methods currently in use is analyzed in detail. A real data illustration is included.</p>","PeriodicalId":16765,"journal":{"name":"Journal of Pharmacokinetics and Biopharmaceutics","volume":"27 4","pages":"437-64"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21670880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}