Comparison of distributed and compartmental models of drug disposition: assessment of tissue uptake kinetics
AbstractThe utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function. With a deviation in th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 17, 2016 Category: Drugs & Pharmacology Source Type: research

PF-05231023, a long-acting FGF21 analogue, decreases body weight by reduction of food intake in non-human primates
Abstract PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure. Here, we present a semi-mechanistic mathematical model of energy balan...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 12, 2016 Category: Drugs & Pharmacology Source Type: research

Steady-state volume of distribution of two-compartment models with simultaneous linear and saturated elimination
Abstract The model-independent estimation of physiological steady-state volume of distribution ( \(V_{dss,p}\) ), often referred to non-compartmental analysis (NCA), is historically based on the linear compartment model structure with central elimination. However the NCA-based steady-state volume of distribution ( \(V_{dss,nca}\) ) cannot be generalized to more complex models. In the current paper, two-compartment models with simultaneous first-order and Michaelis–Menten elimination are considered. In particular, two in...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 12, 2016 Category: Drugs & Pharmacology Source Type: research

Feedback control indirect response models
Abstract A general framework is introduced for modeling pharmacodynamic processes that are subject to autoregulation, which combines the indirect response (IDR) model approach with methods from classical feedback control of engineered systems. The canonical IDR models are modified to incorporate linear combinations of feedback control terms related to the time course of the difference (the error signal) between the pharmacodynamic response and its basal value. Following the well-established approach of traditional engineering control theory, the proposed feedback control indirect response models incorporate terms ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 9, 2016 Category: Drugs & Pharmacology Source Type: research

Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies
In this report, we introduce a simple strategy, employing physiologically-based modeling, to predict mAb disposition in humans. The approach employs estimates of inter-antibody variability in rate processes of extravasation in tissues and fluid-phase endocytosis, estimates for target concentrations in tissues derived through use of categorical immunohistochemical scores, and in vitro measures of the turnover of target and target-mAb complexes. Monte Carlo simulations were performed for four mAbs (cetuximab, figitumumab, dalotuzumab, trastuzumab) directed against three targets (epidermal growth factor receptor, insulin-like...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 4, 2016 Category: Drugs & Pharmacology Source Type: research

The role of stochastic gene switching in determining the pharmacodynamics of certain drugs: basic mechanisms
Abstract In this paper we analyze the impact of the stochastic fluctuation of genes between their ON and OFF states on the pharmacodynamics of a potentially large class of drugs. We focus on basic mechanisms underlying the onset of in vitro experimental dose-response curves, by investigating two elementary molecular circuits. Both circuits consist in the transcription of a gene and in the successive translation into the corresponding protein. Whereas in the first the activation/deactivation rates of the single gene copy are constant, in the second the protein, now a transcription factor, amplifies the deactivation...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 28, 2016 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler
In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 15, 2016 Category: Drugs & Pharmacology Source Type: research

Analysis of peginterferon β-1a exposure and Gd-enhanced lesion or T2 lesion response in relapsing-remitting multiple sclerosis patients
Abstract The effect of subcutaneous (SC) peginterferon β-1a exposure on reduction of gadolinium-enhanced (Gd+) lesion count over time was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in a Phase 3 study (ADVANCE). Patients were randomized to receive SC injections of placebo (n = 500), 125 mcg every-2-weeks (n = 512), or 125 mcg every-4-weeks (n = 500) for 1 year, and then active treatment in the second year. Steady state 4-week AUC (AUCss) was derived for each individual based on sparse pharmacokinetic (PK) sample and a population PK mode...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 14, 2016 Category: Drugs & Pharmacology Source Type: research

The pharmacokinetics of dexmedetomidine during long-term infusion in critically ill pediatric patients. A Bayesian approach with informative priors
Abstract The purpose of this study was to assess the pharmacokinetics of dexmedetomidine in the ICU settings during the prolonged infusion and to compare it with the existing literature data using the Bayesian population modeling with literature-based informative priors. Thirty-eight patients were included in the analysis with concentration measurements obtained at two occasions: first from 0 to 24 h after infusion initiation and second from 0 to 8 h after infusion end. Data analysis was conducted using WinBUGS software. The prior information on dexmedetomidine pharmacokinetics was elicited from the lite...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 24, 2016 Category: Drugs & Pharmacology Source Type: research

Comparing the performance of FOCE and different expectation-maximization methods in handling complex population physiologically-based pharmacokinetic models
This study took everolimus as a model drug and simulated PK data based on published results. Three most popular EM methods (SAEM, IMP and QRPEM) and FOCE (as a benchmark reference) were evaluated for their estimation accuracy and converging speed when solving models of increased complexity. Both sparse and rich sampling data structure were tested. We concluded that FOCE was superior to EM methods for simple structured models. For more complex models and/ or sparse data, EM methods are much more robust. While the estimation accuracy was very close across EM methods, the general ranking of speed (fastest to slowest) was: QRP...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 23, 2016 Category: Drugs & Pharmacology Source Type: research

Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose–response analysis
Abstract PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose–response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. Th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 13, 2016 Category: Drugs & Pharmacology Source Type: research

Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations
In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores. Both approaches improved the model fits significantly. In addition, stochastic simulation and estimation were used to explore further the capability of the two approaches to diagnose and improve models where existing WSV is not recognized. The results of simulations confirmed the gain in introducing WSV as dIOV and SDEs when parameters v...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 10, 2016 Category: Drugs & Pharmacology Source Type: research

Minimal physiologically-based pharmacokinetic (mPBPK) model for a monoclonal antibody against interleukin-6 in mice with collagen-induced arthritis
Abstract Therapeutic monoclonal antibodies (mAb) targeting soluble inflammatory cytokines exert their pharmacological effects in rheumatoid arthritis through binding and neutralizing free cytokines in target tissue sites. Therefore suppression of free cytokines in such sites directly relates to the magnitude of therapeutic response. Although the interrelationships between mAb and cytokines have been examined in the systemic circulation, less is known about the interaction of mAb and cytokines in inflamed joints. In the present study, the interplay between the mAb, CNTO 345, and its target IL-6 in serum as well as ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 27, 2016 Category: Drugs & Pharmacology Source Type: research

Models for the red blood cell lifespan
Abstract The lifespan of red blood cells (RBCs) plays an important role in the study and interpretation of various clinical conditions. Yet, confusion about the meanings of fundamental terms related to cell survival and their quantification still exists in the literature. To address these issues, we started from a compartmental model of RBC populations based on an arbitrary full lifespan distribution, carefully defined the residual lifespan, current age, and excess lifespan of the RBC population, and then derived the distributions of these parameters. For a set of residual survival data from biotin-labeled RBCs, w...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 2, 2016 Category: Drugs & Pharmacology Source Type: research

Organ data from the developing G öttingen minipig: first steps towards a juvenile PBPK model
Abstract The G öttingen minipig is the most commonly used pig breed in preclinical drug development in Europe and has recently also been explored for physiologically based pharmacokinetic modelling. To develop such a model, not only physiological data from adult animals but also data from juvenile animals are req uired, especially when using this model for paediatric drug development. Therefore, the aim of our study was to document body and organ weights (brain, heart, lungs, liver, gastrointestinal tract, spleen and kidney), lengths of the small and large intestines and pH values of the gastrointestinal tra ct i...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 1, 2016 Category: Drugs & Pharmacology Source Type: research

Evaluation of estimation, prediction and inference for autocorrelated latent variable modeling of binary data—a simulation study
Abstract Longitudinal models of binary or ordered categorical data are often evaluated for adequacy by the ability of these to characterize the transition frequency and type between response states. Drug development decisions are often concerned with accurate prediction and inference of the probability of response by time and dose. A question arises on whether the transition probabilities need to be characterized adequately to ensure accurate response prediction probabilities unconditional on the previous response state. To address this, a simulation study was conducted to assess bias in estimation, prediction and...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 23, 2016 Category: Drugs & Pharmacology Source Type: research

Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma
Abstract Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody in development for the treatment of patients with multiple myeloma who have received one or more prior therapies. In this work, 6958 elotuzumab serum concentrations from 375 patients enrolled in four Phase 1 to 3 clinical trials were used to analyze the pharmacokinetics (PK) of elotuzumab. A population PK model with parallel linear and Michaelis–Menten elimination from the central compartment and limited-capacity target-mediated elimination from the peripheral compartment described the elotuzumab concentration–time course. Clearan...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 18, 2016 Category: Drugs & Pharmacology Source Type: research

The performance of model-based versus rule-based phase I clinical trials in oncology
Abstract Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D). Traditionally, phase I trial designs are rule-based, but for several years there is a trend towards model-based designs. Simulations have shown that model-based designs perform better, faster and are safer to establish the RP2D than rule-based designs. However, the superiority of model-based designs has never been confirmed based on true trial performance in practice. To aid evidence-based decisions for designing phase I trials, we compared publications of model-based and ru...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 10, 2016 Category: Drugs & Pharmacology Source Type: research

Accelerating Monte Carlo power studies through parametric power estimation
Abstract Estimating the power for a non-linear mixed-effects model-based analysis is challenging due to the lack of a closed form analytic expression. Often, computationally intensive Monte Carlo studies need to be employed to evaluate the power of a planned experiment. This is especially time consuming if full power versus sample size curves are to be obtained. A novel parametric power estimation (PPE) algorithm utilizing the theoretical distribution of the alternative hypothesis is presented in this work. The PPE algorithm estimates the unknown non-centrality parameter in the theoretical distribution from a limi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 2, 2016 Category: Drugs & Pharmacology Source Type: research

Input estimation for drug discovery using optimal control and Markov chain Monte Carlo approaches
Abstract Input estimation is employed in cases where it is desirable to recover the form of an input function which cannot be directly observed and for which there is no model for the generating process. In pharmacokinetic and pharmacodynamic modelling, input estimation in linear systems (deconvolution) is well established, while the nonlinear case is largely unexplored. In this paper, a rigorous definition of the input-estimation problem is given, and the choices involved in terms of modelling assumptions and estimation algorithms are discussed. In particular, the paper covers Maximum a Posteriori estimates using...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 1, 2016 Category: Drugs & Pharmacology Source Type: research

Model-based meta-analysis for development of a population-pharmacokinetic (PPK) model for Vitamin D3 and its 25OHD3 metabolite using both individual and arm-level data
Abstract Clinical studies investigating relationships between D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of exogenous D3. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a PPK model was developed to predict mean D3 and 25OHD3 exposure from varied doses and administration routes. Sources of exposure variability related to metabolite baseline, weight, and assay type were explored. Specific search criteria were used in PUBMED to identify public source PK data pertaining to D3 and 25OHD3 in healthy or ost...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2016 Category: Drugs & Pharmacology Source Type: research

Methods and strategies for assessing uncontrolled drug–drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group
Abstract The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start an...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 2, 2016 Category: Drugs & Pharmacology Source Type: research

Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects
The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia’s correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1–10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval rel...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 6, 2016 Category: Drugs & Pharmacology Source Type: research

Organ data from the developing Göttingen minipig: first steps towards a juvenile PBPK model
Abstract The Göttingen minipig is the most commonly used pig breed in preclinical drug development in Europe and has recently also been explored for physiologically based pharmacokinetic modelling. To develop such a model, not only physiological data from adult animals but also data from juvenile animals are required, especially when using this model for paediatric drug development. Therefore, the aim of our study was to document body and organ weights (brain, heart, lungs, liver, gastrointestinal tract, spleen and kidney), lengths of the small and large intestines and pH values of the gastrointestinal tr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 19, 2015 Category: Drugs & Pharmacology Source Type: research

A strategy for residual error modeling incorporating scedasticity of variance and distribution shape
In conclusion, the use of dTBS and/or t-distribution models provides a flexible and easy-to-use framework capable of characterizing all commonly encountered residual error distributions. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 17, 2015 Category: Drugs & Pharmacology Source Type: research

Determination of a suitable voriconazole pharmacokinetic model for personalised dosing
Abstract Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a ‘hybrid’ model for voriconazole that incorporated information from prior models in a biologically plausible manner. Vorico...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 16, 2015 Category: Drugs & Pharmacology Source Type: research

What do we mean by identifiability in mixed effects models?
Abstract We discuss the question of model identifiability within the context of nonlinear mixed effects models. Although there has been extensive research in the area of fixed effects models, much less attention has been paid to random effects models. In this context we distinguish between theoretical identifiability, in which different parameter values lead to non-identical probability distributions, structural identifiability which concerns the algebraic properties of the structural model, and practical identifiability, whereby the model may be theoretically identifiable but the design of the experiment may ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 10, 2015 Category: Drugs & Pharmacology Source Type: research

A population pharmacokinetic model for R- and S-citalopram and desmethylcitalopram in Alzheimer’s disease patients with agitation
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 S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower tha...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 26, 2015 Category: Drugs & Pharmacology Source Type: research

Erratum to: Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 23, 2015 Category: Drugs & Pharmacology Source Type: research

Stochastic nonlinear mixed effects: a metformin case study
This article focuses on implementing the extended Kalman filter and unscented Kalman filter in an NLME framework for parameter estimation and model development, comparing the methodologies, and illustrating their challenges and utility. The Kalman filter algorithms were successfully implemented in NLME models using MATLAB with run time differences between the ODE and SDE methods comparable to the differences found by Kakhi [10] for their stochastic deconvolution. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 19, 2015 Category: Drugs & Pharmacology Source Type: research

Model-based approaches for ivabradine development in paediatric population, part II: PK and PK/PD assessment
The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 14, 2015 Category: Drugs & Pharmacology Source Type: research

Application of a hazard-based visual predictive check to evaluate parametric hazard models
Abstract Parametric models used in time to event analyses are evaluated typically by survival-based visual predictive checks (VPC). Kaplan–Meier survival curves for the observed data are compared with those estimated using model-simulated data. Because the derivative of the log of the survival curve is related to the hazard—the typical quantity modeled in parametric analysis—isolation, interpretation and correction of deficiencies in the hazard model determined by inspection of survival-based VPC’s is indirect and thus more difficult. The purpose of this study is to assess the performance o...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 13, 2015 Category: Drugs & Pharmacology Source Type: research

Model-based approaches for ivabradine development in paediatric population, part I: study preparation assessment
Abstract The main objective was to help design a paediatric study for ivabradine, a compound already marketed in adults, focusing on: the paediatric formulation evaluation, the doses to be administered, the sampling design and the sampling technique. A secondary objective was to perform a comparison of the prediction of ivabradine pharmacokinetics (PK) in children using a physiologically-based pharmacokinetic (PBPK) approach and allometric scaling of a population pharmacokinetic (PPK) model. A study was conducted in order to assess the relative bioavailability (Frel) of the paediatric formulation and a similar...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 12, 2015 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics of ramosetron
This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19–80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM®). The pharmacok...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 11, 2015 Category: Drugs & Pharmacology Source Type: research

Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis
Abstract Improving the quality of exposure–response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and pla...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 9, 2015 Category: Drugs & Pharmacology Source Type: research

Study design and population pharmacokinetic analysis of a phase II dose-ranging study of interleukin-1 receptor antagonist
Abstract Interleukin-1 receptor antagonist, a naturally-occurring antagonist to the pro-inflammatory cytokine Interleukin-1, is already in clinical use. In experimental models of stroke, Interleukin-1 receptor antagonist in cerebrospinal fluid has been associated with cerebral neuroprotection and in a phase I clinical trial in patients with subarachnoid haemorrhage it crosses the blood-cerebrospinal fluid barrier. The aims of the current work were to design a dose-ranging clinical study in patients and to analyse the plasma and cerebrospinal fluid data obtained using a population pharmacokinetic modelling approach...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 18, 2015 Category: Drugs & Pharmacology Source Type: research

Inter occasion variability in individual optimal design
Abstract Inter occasion variability (IOV) is of importance to consider in the development of a design where individual pharmacokinetic or pharmacodynamic parameters are of interest. IOV may adversely affect the precision of maximum a posteriori (MAP) estimated individual parameters, yet the influence of inclusion of IOV in optimal design for estimation of individual parameters has not been investigated. In this work two methods of including IOV in the maximum a posteriori Fisher information matrix (FIMMAP) are evaluated: (i) MAPocc—the IOV is included as a fixed effect deviation per occasion and individual, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2015 Category: Drugs & Pharmacology Source Type: research

Perspectives on the history and scientific contributions of Gerhard Levy
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 25, 2015 Category: Drugs & Pharmacology Source Type: research

Preface to the special issue to honor Gerhard Levy and 50 years of PK/PD
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 25, 2015 Category: Drugs & Pharmacology Source Type: research

A population PK model for citalopram and its major metabolite, N-desmethyl citalopram, in rats
Abstract A population PK model was developed in order to simultaneously describe citalopram and its major metabolite, n-desmethyl citalopram, plasma concentrations in two different strain of rats after intravenous (IV) and oral (PO) administration of citalopram. Citalopram was administered to Sprague–Dawley (SD) rats at doses: 0.3, 1, 3, and 10 mg/kg IV and 10 mg/kg PO. The compound was dosed orally to Wistar rats at doses: 0.3, 1, 3, 10, 30 and 60 mg/kg. Plasma samples were collected for citalopram and metabolite. Pharmacokinetic analyses were conducted using NONMEM 7.2. Values below the quan...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 22, 2015 Category: Drugs & Pharmacology Source Type: research

Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice
Abstract Bortezomib is a reversible proteasome inhibitor with potent antineoplastic activity that exhibits dose- and time-dependent pharmacokinetics (PK). Proteasome-mediated bortezomib disposition is proposed as the primary source of its nonlinear and apparent nonstationary PK behavior. Single intravenous (IV) doses of bortezomib (0.25 and 1 mg/kg) were administrated to BALB/c mice, with blood and tissue samples obtained over 144 h, which were analyzed by LC/MS/MS. A physiologically based pharmacokinetic (PBPK) model incorporating tissue drug-target binding was developed to test the hypothesis of protea...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 21, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic models of age-structured cell populations
Abstract The purpose of this work is to review basic pharmacodynamic (PD) models describing drug effects on cell populations and expand them to age-structured models using the theory of physiologically structured populations. The plasma drug concentrations are interpreted as the environment affecting the cell production and mortality rates. An explicit solution to model equations provides the age density distribution that serves to establish a relationship between the cell lifespan distribution and the hazard of cell removal. Given the lifespan distributions, the age distributions for most commonly applied PD mode...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 16, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics
Abstract Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biologi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

Abstracts Accepted for American Conference on Pharmacometrics 2015 (ACoP6)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

The American Conference on Pharmacometrics 2015 (ACoP6)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

Program
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys
Abstract Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 12, 2015 Category: Drugs & Pharmacology Source Type: research

Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l -lactate in rats
In conclusion, we developed a semi-mechanistic kidney model that can be used to evaluate transporter-mediated active renal reabsorption of drugs by the kidney. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice
Abstract A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization. The cytotoxic effects of treatment were described by the kinetics ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

Prediction and validation of enzyme and transporter off-targets for metformin
In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved in the intestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 3, 2015 Category: Drugs & Pharmacology Source Type: research