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 characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CL(D) decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.
journal_name
J Pharmacokinet Pharmacodynjournal_title
Journal of pharmacokinetics and pharmacodynamicsauthors
Mager DE,Jusko WJdoi
10.1023/a:1014414520282keywords:
subject
Has Abstractpub_date
2001-12-01 00:00:00pages
507-32issue
6eissn
1567-567Xissn
1573-8744journal_volume
28pub_type
杂志文章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：:Ordinary differential equation models often contain a large number of parameters that must be determined from measurements by estimation procedure. For an estimation to be successful there must be a unique set of parameters that can have produced the measured data. This is not the case if a model is not structurally i...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-019-09624-9
更新日期：2019-04-01 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：:We develop a mechanistic model for post-operative pain and apply it to describe the pharmacodynamic effects of the kappa-opioids nalbuphine and naloxone administered either alone or in combination in patients after surgical removal of one or more madibular third molar teeth. Data were obtained from 6 clinical studies ...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章,随机对照试验
doi：10.1007/s10928-007-9076-y
更新日期：2008-02-01 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：: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：: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：: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
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：: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：: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：: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：:The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model w...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-016-9486-9
更新日期：2017-04-01 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：:Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodat...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-014-9374-0
更新日期：2014-12-01 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：: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：: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 aim of this simulation study was to present a system-approach method for adjustment of continuous drug infusions at time-varying rates, aimed at achieving and then maintaining required drug concentration-time profiles in patients. The method presented can be used for safe and cost-effective individualization of dr...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：
更新日期：2002-12-01 00:00:00
abstract：:Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this wor...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-017-9521-5
更新日期：2017-08-01 00:00:00
abstract：:In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol sup...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-006-9013-5
更新日期：2006-08-01 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：:The conventional convection-dispersion model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver bloodflow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1023/a:1019703607647
更新日期：2002-04-01 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：:Bridging fundamental approaches to model optimization for pharmacometricians, systems pharmacologists and statisticians is a critical issue. These fields rely primarily on Maximum Likelihood and Extended Least Squares metrics with iterative estimation of parameters. Our research combines adaptive chaos synchronization...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1007/s10928-019-09629-4
更新日期：2019-04-01 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：: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：: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：:Several reviews on specific topics related to positron emission tomography (PET) ranging in complexity from introductory to highly technical have already been published. This introduction to the analysis of PET data was written as a simple guide of the different phases of analysis of a given PET dataset, from acquisit...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章,评审
doi：10.1007/s10928-013-9307-3
更新日期：2013-08-01 00:00:00
abstract：:Mixture modeling within the context of pharmacokinetic (PK)/pharmacodynamic (PD) mixed effects modeling is a useful tool to explore a population for the presence of two or more subpopulations, not explained by evaluated covariates. At present, statistical tests for the existence of mixed populations have not been deve...
journal_title：Journal of pharmacokinetics and pharmacodynamics
pub_type： 杂志文章
doi：10.1023/a:1025564409649
更新日期：2003-06-01 00:00:00
