Abstract:
:A number of experimental observations in the late 1960s, early 1970s could not be explained by the pharmacokinetic theory available at that time. For example rats receiving phenobarbital as an enzyme inducing agent exhibited increased elimination of phenylbutazone in vitro in liver microsomes and in vivo in whole animals compared to that observed in non-induced animals. However, for desipramine, although phenobarbital increased elimination in microsomes, no change in plasma disappearance was noted in vivo for this drug between rats induced with phenobarbital and control rats. Similar in vitro-in vivo discordancies were seen with changes in protein binding. The introduction of clearance concepts in the early 1970s by Professor Rowland and others provided the scientific rationale for these apparently contradictory findings and the recognition that clearance, not half-life, was the measure of the body's ability to eliminate drugs and most importantly that changes in pathology and physiology could be correlated with measures of clearance. Up to that time half-life was well recognized in terms of basic chemical principles as an appropriate measure of the rate of elimination and reflective of changes in the rate of elimination. The difference between chemistry and pharmacokinetics, however, is that in chemistry the volume in which the reaction occurs does not change. In contrast, in pharmacokinetics, disease states and differences in physiology can change the space available in which the drug may distribute in the body. Thus, it was necessary to develop a pharmacokinetic measure of volume that was independent of elimination, i.e., V(ss). Now, the relationship between V(ss) and clearance led to a unique measure of time of drug in the body, the mean residence time. Although this parameter is calculated in all PK programs, very few pharmaceutical scientists know how it can be useful. Very recently, we have shown that the concepts of accumulation, prediction of which is the clinically relevant use for half-life and mean residence time, are flawed and that the appropriate time dependent parameter to predict accumulation has not been previously correctly identified. Finally, when clearance concepts were developed our understanding of the importance of drug transporters was nonexistent. A critical, and generally unrecognized assumption (which is only explicitly stated in Professor Rowland's seminal 1973 paper), in the development of the theory of clearance is that the unbound drug concentration in the organ of elimination is in a constant equilibrium with the unbound drug concentration in the systemic circulation, where drug concentration measurements are made. Transporter drug-drug and disease interactions may, in fact, change this equilibrium and potentially what we consider as intrinsic clearance, may not be independent of an eliminating organ volume parameter, contrary to what we have been teaching for the past 37 years.
journal_name
J Pharmacokinet Pharmacodynjournal_title
Journal of pharmacokinetics and pharmacodynamicsauthors
Benet LZdoi
10.1007/s10928-010-9187-8subject
Has Abstractpub_date
2010-12-01 00:00:00pages
529-39issue
6eissn
1567-567Xissn
1573-8744journal_volume
37pub_type
杂志文章,评审abstract::Development of novel therapies for bone diseases can benefit from mathematical models that predict drug effect on bone remodeling biomarkers. Therefore, a bone cycle model (BCM) was developed that takes into consideration the concept of the basic multicellular unit and the dynamic equilibrium of bone remodeling. The m...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-015-9423-3
更新日期:2015-08-01 00:00:00
abstract::To solve the problem of estimating an unknown input function to a linear time invariant system we propose an adaptive non-parametric method based on reversible jump Markov chain Monte Carlo (RJMCMC). We use piecewise polynomial functions (splines) to represent the input function. The RJMCMC algorithm allows the explor...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-006-9045-x
更新日期:2007-06-01 00:00:00
abstract::Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-018-9612-y
更新日期:2019-02-01 00:00:00
abstract::The utilisation of physiologically-based pharmacokinetic models for the analysis of population data is an approach with progressively increasing impact. However, as we move from empirical to complex mechanistic model structures, incorporation of stochastic variability in model parameters can be challenging due to the ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-015-9418-0
更新日期:2015-08-01 00:00:00
abstract::There are situations in drug development where one may wish to reduce the dimensionality and complexity of whole body physiologically based pharmacokinetic models. A technique for formal reduction of such models, based on global sensitivity analysis, is suggested. Using this approach mean and variance of tissue(s) and...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-005-0004-8
更新日期:2006-02-01 00:00:00
abstract::There have been no pharmacokinetic parameters and blood-brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Statu...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-015-9408-2
更新日期:2015-04-01 00:00:00
abstract::Target-mediated drug disposition (TMDD) is frequently reported for therapeutic monoclonal antibodies and is linked to the high affinity and high specificity of antibody molecules for their target. Understanding TMDD of a monoclonal antibody should go beyond the empirical description of its non-linear PK since valuable...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章,评审
doi:10.1007/s10928-009-9129-5
更新日期:2009-10-01 00:00:00
abstract::Cancer therapies that harness the actions of the immune response, such as targeted monoclonal antibody treatments and therapeutic vaccines, are relatively new and promising in the landscape of cancer treatment options. Mathematical modeling and simulation of immune-modifying therapies can help to offset the costs of d...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-014-9386-9
更新日期:2014-10-01 00:00:00
abstract::Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-018-9589-6
更新日期:2018-06-01 00:00:00
abstract::The volume of distribution at steady state (Vss) of therapeutic proteins is usually assessed by non-compartmental or compartmental pharmacokinetic (PK) analysis wherein errors may arise due to the elimination of therapeutic proteins from peripheral tissues that are not in rapid equilibrium with the sampling compartmen...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-011-9209-1
更新日期:2011-10-01 00:00:00
abstract::A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture ra...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-017-9551-z
更新日期:2017-12-01 00:00:00
abstract::Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-006-9008-2
更新日期:2006-06-01 00:00:00
abstract::We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including p...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-014-9369-x
更新日期:2014-08-01 00:00:00
abstract::This study was designed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) risk factors preceding the onset of type 2 diabetes using a population-based Bayesian nonlinear hierarchical model to describe the glucose-insulin kinetics. One hundred fifty-two healthy subjects with a family history of type 2 diabet...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-009-9130-z
更新日期:2009-10-01 00:00:00
abstract::The study aimed to characterize the population pharmacokinetics of amodiaquine (AQ) and its major metabolite N-desethylamodiaquine (N-DEAQ), and to assess the correlation between exposure to N-DEAQ and treatment outcome. Blood samples from children in two studies in Zanzibar and one in Papua New Guinea were included i...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-007-9064-2
更新日期:2007-10-01 00:00:00
abstract::Neutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (Cmin) required for target engagement. Dose, frequency and PK...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-019-09667-y
更新日期:2020-02-01 00:00:00
abstract::To shed light on how acute exercise affects blood glucose (BG) concentrations in nondiabetic subjects, we develop a physiological pharmacokinetic/pharmacodynamic model of postprandial glucose dynamics during exercise. We unify several concepts of exercise physiology to derive a multiscale model that includes three imp...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-020-09726-9
更新日期:2021-01-04 00:00:00
abstract::Mathematical modeling of drug effects maximizes the information gained from an experiment, provides further insight into the mechanisms of drug effects, and allows for simulations in order to design studies or even to derive clinical treatment strategies. We reviewed modeling of antimicrobial drug effects and show tha...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章,评审
doi:10.1007/s10928-007-9069-x
更新日期:2007-12-01 00:00:00
abstract::The majority of measures proposed to date for direct curve comparison in bioequivalence studies were investigated. These measures have often been called metrics, but in most cases this was incorrect in the mathematical sense. It was demonstrated, with a set of counter-examples, that the axioms of a metric are fulfille...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-009-9121-0
更新日期:2009-06-01 00:00:00
abstract::Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug cle...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-011-9213-5
更新日期:2011-10-01 00:00:00
abstract::The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-018-9575-z
更新日期:2018-04-01 00:00:00
abstract::Significant arterio-venous differences in nicotine concentrations have been observed during and after cigarette smoking, nicotine nasal spray, and intravenous nicotine administration. In this paper we describe a novel mathematical method for estimating arterial blood levels from venous blood level data. The model allo...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1023/a:1020957208071
更新日期:2002-08-01 00:00:00
abstract::Intravenous acetaminophen is a commonly used analgesic following surgery. The aims of this study were to determine the population pharmacokinetic profile of intravenous acetaminophen and its metabolites in adult surgical patients and to identify patient characteristics associated with acetaminophen metabolism in the p...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-014-9358-0
更新日期:2014-06-01 00:00:00
abstract::We investigated the propagation of population pharmacokinetic information across clinical studies by applying Bayesian techniques. The aim was to summarize the population pharmacokinetic estimates of a study in appropriate statistical distributions in order to use them as Bayesian priors in consequent population pharm...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-005-0048-9
更新日期:2005-08-01 00:00:00
abstract::A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PF-06804103 and T-DM1 was determined across a range of...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-020-09702-3
更新日期:2020-10-01 00:00:00
abstract::The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol-Taxol®) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-018-9586-9
更新日期:2018-08-01 00:00:00
abstract::We propose an efficient algorithm for screening covariates in population model building using Wald's approximation to the likelihood ratio test (LRT) statistic in conjunction with Schwarz's Bayesian criterion. The algorithm can be applied to a full model fit of k covariate parameters to calculate the approximate LRT f...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1023/a:1011579109640
更新日期:2001-06-01 00:00:00
abstract::Age-structured cell population model was introduced to describe cell survival. The impact of the environment on the cell population is represented by drug plasma concentration. A key model variable is the hazard of cell removal that is a subject to the environment effect. The model is capable of describing cohort and ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-017-9520-6
更新日期:2017-08-01 00:00:00
abstract::The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equati...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-017-9546-9
更新日期:2018-02-01 00:00:00
abstract::During the course of therapeutic drug monitoring (TDM), doses are adjusted to attain a target concentration range and a correlation between clearance (CL) and dose is introduced. In population pharmacokinetic analyses of such TDM data, CL has frequently been modeled as a function of dose. This paper demonstrates by si...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-005-0083-6
更新日期:2005-12-01 00:00:00