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 9, 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 26, 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 1, 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 - March 31, 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 22, 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 24, 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 24, 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

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models
The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984–1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 30, 2015 Category: Drugs & Pharmacology Source Type: research

Bayesian population modeling of drug dosing adherence
Abstract Adherence is a frequent contributing factor to variations in drug concentrations and efficacy. The purpose of this work was to develop an integrated population model to describe variation in adherence, dose-timing deviations, overdosing and persistence to dosing regimens. The hybrid Markov chain–von Mises method for modeling adherence in individual subjects was extended to the population setting using a Bayesian approach. Four integrated population models for overall adherence, the two-state Markov chain transition parameters, dose-timing deviations, overdosing and persistence were formulated and cr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 29, 2015 Category: Drugs & Pharmacology Source Type: research

Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
Abstract Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 28, 2015 Category: Drugs & Pharmacology Source Type: research

Modeling population heterogeneity in viral dynamics for chronic hepatitis C infection: Insights from Phase 3 telaprevir clinical studies
Abstract Viral dynamic modelling has proven useful for designing clinical studies and predicting treatment outcomes for patients infected with the hepatitis C virus. Generally these models aim to capture and predict the on-treatment viral load dynamics from a small study of individual patients. Here, we explored extending these models (1) to clinical studies with numerous patients and (2) by incorporating additional data types, including sequence data and prior response to interferon. Data from Phase 3 clinical studies of the direct-acting antiviral telaprevir (T; total daily dose of 2250 mg) combined with pe...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 19, 2015 Category: Drugs & Pharmacology Source Type: research

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities
Abstract Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is develop...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 11, 2015 Category: Drugs & Pharmacology Source Type: research

Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells
Abstract Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 8, 2015 Category: Drugs & Pharmacology Source Type: research

Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics
Abstract Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug–drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanisti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2015 Category: Drugs & Pharmacology Source Type: research

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times
Abstract Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse samplin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 26, 2015 Category: Drugs & Pharmacology Source Type: research

Biomarker- versus drug-driven tumor growth inhibition models: an equivalence analysis
Abstract The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic–pharmacodynamic (PK–PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor gro...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 26, 2015 Category: Drugs & Pharmacology Source Type: research

Identifiability of PBPK models with applications to dimethylarsinic acid exposure
Abstract Any statistical model should be identifiable in order for estimates and tests using it to be meaningful. We consider statistical analysis of physiologically-based pharmacokinetic (PBPK) models in which parameters cannot be estimated precisely from available data, and discuss different types of identifiability that occur in PBPK models and give reasons why they occur. We particularly focus on how the mathematical structure of a PBPK model and lack of appropriate data can lead to statistical models in which it is impossible to estimate at least some parameters precisely. Methods are reviewed which can deter...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 21, 2015 Category: Drugs & Pharmacology Source Type: research

A PBPK model describing a xenobiotic with a short PK event scale
Abstract Physiologically-based pharmacokinetic (PBPK) modeling has been widely used in human risk assessment and in early drug development to predict human PK from in vitro and/or in vivo animal data. Recently, the application of PBPK modeling has been extended to the evaluation of drug–drug interactions. For most xenobiotic agents, the PK event scale such as elimination is in hours or days. This is much longer than the transit time of the agent in the body, and a PBPK model can be significantly simplified through lumping based on the physiochemical properties, mass transfer, and biotransformation. However, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 9, 2015 Category: Drugs & Pharmacology Source Type: research