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 allows to quantify: (i) the influence of the microcirculation in the hands and forearm on the distribution of nicotine, and (ii) the influence of disregarding the venous to arterial circulation in the estimate of systemic inputs. We also (iii) propose a general method to predict arterial concentrations and inputs given venous data. The basic model we adopt is based on the relationship Cv = T * Ca, where Cv and Ca are the concentration in the venous and arterial site, respectively, T is the arterio-venous transfer function and * indicates convolution. We use empirical data to estimate T. We then compare estimates of systemic inputs to the venous site obtained taking into account the transfer function or, as usually done, disregarding it. The relationship we use to compare estimated inputs are: Cv = T * ka * A (where Ka is the arterial disposition function and A the systemic input), and Cv = Kv * A (where Kv is the venous disposition function), respectively. Finally, the estimated transfer function allows to estimate (average) Ca or A given arbitrary venous data. (i) Our analysis suggests that a bi-exponential T is needed to describe observed arterial-venous differences. The estimated transfer function indicates that no elimination of nicotine is involved in the forearm. (ii) Disregarding T, as usually done, erroneously obtains too complex venous input functions (because these input functions incorporate T). (iii) Disregarding T erroneously estimates significantly higher total inputs. (iv) Using the proposed model and previously published venous nicotine level data we predict substantial arterial-venous differences in blood nicotine levels for smokeless tobacco and nicotine gum. The use of disposition functions obtained from venous data may lead to erroneous estimation of the rates of entry into the circulation and systemic bioavailability for many drugs.
journal_name
J Pharmacokinet Pharmacodynjournal_title
Journal of pharmacokinetics and pharmacodynamicsauthors
Pitsiu M,Gries JM,Benowitz N,Gourlay SG,Verotta Ddoi
10.1023/a:1020957208071keywords:
subject
Has Abstractpub_date
2002-08-01 00:00:00pages
383-402issue
4eissn
1567-567Xissn
1573-8744journal_volume
29pub_type
杂志文章abstract::Previously, we developed a feedback model to describe the tolerance and oscillatory rebound of non-esterified fatty acid (NEFA) plasma concentrations in male Sprague Dawley rats after intravenous infusions of nicotinic acid (NiAc). This study challenges that model, using the following regimens of intravenous and oral ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-013-9325-1
更新日期:2013-08-01 00:00:00
abstract::Literature data are often reported as multiple (longitudinal) mean outcomes observed in several groups of patients within a study. Observations within a study are correlated because the patients come from a common population, and the mean observations over time within a treatment arm are correlated because they are ba...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-010-9152-6
更新日期:2010-04-01 00:00:00
abstract::We explored the type I error rate (false positive rate) associated with exposure-response (ER) analyses for two compounds in a fixed-dose combination product through simulations. In the simulations, at least one compound was assumed to be inactive, whereas the active compound followed E(max) model at different concent...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-011-9214-4
更新日期:2011-12-01 00:00:00
abstract::This study developed an integrated model of severity scores of migraine headache and the incidence of nausea, photophobia, and phonophobia to predict the natural time course of migraine symptoms, which are likely to occur by a common disease progression mechanism. Data were acquired from two phase 3 clinical trials co...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10928-018-9602-0
更新日期:2018-10-01 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::We explore the use of fractional order differential equations for the analysis of datasets of various drug processes that present anomalous kinetics, i.e. kinetics that are non-exponential and are typically described by power-laws. A fractional differential equation corresponds to a differential equation with a deriva...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-009-9116-x
更新日期:2009-04-01 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::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 citalopram for Alzheimer's disease trial evaluated citalopram for the management for agitation in Alzheimer's disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-015-9457-6
更新日期:2016-02-01 00:00:00
abstract::HER2-positive breast cancer (BC) is a rapidly growing and aggressive BC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitative systems pharmacological ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-020-09732-x
更新日期:2021-01-03 00:00:00
abstract::Assessment of the elimination of an oral test dose based on plasma concentration values requires correction for the effect of gastric release and absorption. Irregular uptake processes should be described 'model independently', which requires estimation of a large number of absorption parameters. To limit the associat...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-013-9299-z
更新日期:2013-04-01 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::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::Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA) scores. Throu...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-018-9581-1
更新日期:2018-08-01 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::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::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::A method based on the multivariate technique known as principal component analysis is proposed to obtain starting values for the rate constants of indirect response models. The method is not iterative and only requires standard deviation calculations for two quantities, which are simple functions of the measured pharm...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1023/b:jopa.0000029487.21238.5c
更新日期:2004-02-01 00:00:00
abstract::Long term therapy with antiretroviral agents in HIV-infected patients often result in failure to suppress the virus load. Imperfect adherence to prescribed antiviral drugs is an important factor explaining the resurgence of virus. A better understanding of the factors responsible for the virological failure is importa...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-006-9022-4
更新日期:2006-08-01 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::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::There has been little evaluation of maximum likelihood approximation methods for non-linear mixed effects modelling of count data. The aim of this study was to explore the estimation accuracy of population parameters from six count models, using two different methods and programs. Simulations of 100 data sets were per...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-009-9126-8
更新日期:2009-08-01 00:00:00
abstract::In this work a model for analyzing categorical data is presented; the differential odds model. Unlike the commonly used proportional odds model, this model does not assume that a covariate affects all categories equally on the log odds scale. The differential odds model was compared to the proportional odds model, by ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-008-9098-0
更新日期:2008-10-01 00:00:00
abstract::T cell responses are a crucial part of the adaptive immune system in the fight against infections. This article discusses the use of mathematical models for understanding the dynamics of cytotoxic T lymphocyte (CTL) responses against viral infections. Complementing experimental research, mathematical models have been ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章,评审
doi:10.1007/s10928-014-9387-8
更新日期:2014-10-01 00:00:00
abstract::Mixture models are applied in population pharmacometrics to characterize underlying population distributions that are not adequately approximated by a single normal or lognormal distribution. In addition to obtaining individualized maximum a posteriori Bayesian post hoc parameter estimates, the subpopulation to which ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 临床试验,杂志文章
doi:10.1007/s10928-006-9038-9
更新日期:2007-04-01 00:00:00
abstract::A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/k...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-007-9049-1
更新日期:2007-06-01 00:00:00
abstract::The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1007/s10928-017-9555-8
更新日期:2018-04-01 00:00:00
abstract::Structural identifiability is an often overlooked, but essential, prerequisite to the experiment design stage. The application of structural identifiability analysis to models of myelosuppression is used to demonstrate the importance of its considerations. It is shown that, under certain assumptions, these models are ...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章,meta分析
doi:10.1007/s10928-018-9569-x
更新日期:2018-02-01 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::Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characteriz...
journal_title:Journal of pharmacokinetics and pharmacodynamics
pub_type: 杂志文章
doi:10.1023/a:1014414520282
更新日期:2001-12-01 00:00:00