A modeling and simulation-based assessment of the impact of confounding factors on the readout of a sildenafil survival trial in pulmonary arterial hypertension
AbstractSildenafil (REVATIO®) was approved for the treatment of adult Pulmonary Arterial Hypertension (PAH) in the US and the EU. A pediatric study has been performed and sildenafil was approved in the EU for pediatric PAH. The long-term extension of this study revealed good survival but also an increased mortality with the high dose of sildenafil compared to lower doses. As a consequence, FDA required Pfizer to evaluate REVATIO®’s effect on the risk of death in adults with PAH. Following FDA’s rationale a survival model was developed to characterize the exposure–mortality relationship and assess ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 19, 2019 Category: Drugs & Pharmacology Source Type: research

A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia
AbstractCystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 6, 2019 Category: Drugs & Pharmacology Source Type: research

Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients
AbstractUlcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standa...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2019 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation of the modified Rankin Scale and National Institutes of Health Stroke Scale neurological endpoints in intracerebral hemorrhage
AbstractIntracerebral hemorrhage (ICH) is a form of stroke characterized by uncontrolled bleeding into the parenchyma of the brain. There is no approved therapy for ICH and it is associated with very poor neurological outcomes with around half of subjects dying within 1  month and most subjects showing complete or partial disability. A key challenge is to identify subjects who could benefit from intervention using characteristics such as baseline hemorrhage volume and the increase in hemorrhage volume in the first few hours, which have been correlated with final o utcomes in ICH. Combined longitudinal models were deve...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 28, 2019 Category: Drugs & Pharmacology Source Type: research

A quantitative systems pharmacology model of colonic motility with applications in drug development
AbstractWe developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defec...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 19, 2019 Category: Drugs & Pharmacology Source Type: research

Concentration –response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent
AbstractThe effects of contezolid (MRX-I, an oxazolidinone antibacterial agent) on cardiac repolarization were evaluated retrospectively using a population modeling approach in a Phase I study incorporating single ascending dose, multiple ascending dose, and food effect assessments. Linear mixed effect models were used to assess the relationships between MRX-I plasma concentrations and QT/QTc/ ∆QTc (baseline-adjusted), in which different correction methods for heart rate have been included. The upper bound of the one-sided 95% confidence interval (CI) for predicted ∆∆QTc was 
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 12, 2019 Category: Drugs & Pharmacology Source Type: research

Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes
AbstractThe primary goal of this work was to develop a computational tool to enable personalized prediction of pharmacological disposition and associated responses for opioids and antidotes. Here we present a computational framework for physiologically-based pharmacokinetic (PBPK) modeling of an opioid (morphine) and an antidote (naloxone). At present, the model is solely personalized according to an individual ’s mass. These PK models are integrated with a minimal pharmacodynamic model of respiratory depression induction (associated with opioid administration) and reversal (associated with antidote administration). ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 7, 2019 Category: Drugs & Pharmacology Source Type: research

Orphan drug development: the increasing role of clinical pharmacology
AbstractOver the last few decades there has been a paradigm shift in orphan drug research and development. The development of the regulatory framework, establishment of rare disease global networks that support drug developments, and advances in technology, has resulted in tremendous growth in orphan drug development. Nevertheless, several challenges during orphan drug development such as economic constraints; insufficient clinical information; fewer patients and thus inadequate power; etc. still exist. While the standard regulatory requirements for drug approval stays the same, applications of scientific judgment and regu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 22, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients
The article Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients, written by Pierre Chelle, Cindy H. T. Yeung, Santiago Bonanad, Juan Crist óbal Morales Muñoz, Margareth C. Ozelo, Juan Eduardo Megías Vericat, Alfonso Iorio, Jeffrey Spears, Roser Mir, Andrea Edginton, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 21 May 2019 without open access. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 12, 2019 Category: Drugs & Pharmacology Source Type: research

FDA ’s Office of Orphan Products Development: providing incentives to promote the development of products for rare diseases
AbstractThere are nearly 30 million Americans that suffer from at least one of the more than 7000 rare diseases identified to date. Therapies for treating, preventing, or diagnosing rare diseases have been limited due to various reasons. Incentives are provided to sponsors in an effort to promote the development of therapies for rare diseases and to encourage the availability of therapeutically superior drugs or biologics. This paper will discuss the mission of the Office of Orphan Products Development within the Food and Drug Administration (FDA), the specific programs within the office and the relation to incentives prov...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 4, 2019 Category: Drugs & Pharmacology Source Type: research

Automated proper lumping for simplification of linear physiologically based pharmacokinetic systems
AbstractPhysiologically based pharmacokinetic (PBPK) models are an important type of systems model used commonly in drug development before commencement of first-in-human studies. Due to structural complexity, these models are not easily utilised for future data-driven population pharmacokinetic (PK) analyses that require simpler models. In the current study we aimed to explore and automate methods of simplifying PBPK models using a proper lumping technique. A linear 17-state PBPK model for fentanyl was identified from the literature. Four methods were developed to search the optimal lumped model, including full enumeratio...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 20, 2019 Category: Drugs & Pharmacology Source Type: research

Bayesian approach to investigate a two-state mixed model of COPD exacerbations
AbstractChronic obstructive pulmonary disease (COPD) is a chronic obstructive disease of the airways. An exacerbation of COPD is defined as shortness of breath, cough, and sputum production. New therapies for COPD exacerbations are examined in clinical trials frequently based on the number of exacerbations that implies long-term study due to the high variability in occurrence and duration of the events. In this work, we expanded the two-state model developed by Cook et al. where the patient transits from an asymptomatic (state 1) to a symptomatic state (state 2) and vice versa, through investigating different semi-Markov m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 12, 2019 Category: Drugs & Pharmacology Source Type: research

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy
AbstractDrug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such too...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 23, 2019 Category: Drugs & Pharmacology Source Type: research

A translational platform PBPK model for antibody disposition in the brain
AbstractIn this manuscript, we have presented the development of a novel platform physiologically-based pharmacokinetic (PBPK) model to characterize brain disposition of mAbs in the mouse, rat, monkey and human. The model accounts for known anatomy and physiology of the brain, including the presence of distinct blood –brain barrier and blood–cerebrospinal fluid (CSF) barrier. CSF and interstitial fluid turnover, and FcRn mediated transport of mAbs are accounted for. The model was first used to characterize published and in-house pharmacokinetic (PK) data on the disposition of mAbs in rat brain, including the da...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 20, 2019 Category: Drugs & Pharmacology Source Type: research

Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients
This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 20, 2019 Category: Drugs & Pharmacology Source Type: research

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization
AbstractHemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Computer-assembled cross-species/cross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats
AbstractTwo-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 10, 2019 Category: Drugs & Pharmacology Source Type: research

Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems
AbstractGuiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric (Stein and Ramakrishna in CPT Pharmacomet Syst Pharmacol 6(4):258 –266, 2017) is extended to include a “target-tissue” compartment and the shedding of membrane-bound targets. A new potency metric average free tissue target to initial target ratio (AFTIR) at steady state is derived, and it depends on only four key quantities: the equilib...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 28, 2019 Category: Drugs & Pharmacology Source Type: research

Two-pore physiologically based pharmacokinetic model with de novo derived parameters for predicting plasma PK of different size protein therapeutics
AbstractTwo-pore PBPK models have been used for characterizing the PK of protein therapeutics since 1990s. However, widespread utilization of these models is hampered by the lack of a priori parameter values, which are typically estimated using the observed data. To overcome this hurdle, here we have presented the development of a two-pore PBPK model using de novo derived parameters. The PBPK model was validated using plasma PK data for different size proteins in mice. Using the “two pore theory” we were able to establish the relationship between protein size and key model parameters, such as: permeability-surf...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 25, 2019 Category: Drugs & Pharmacology Source Type: research

Operating characteristics of stepwise covariate selection in pharmacometric modeling
AbstractStepwise covariate modeling (SCM) is a widely used tool in pharmacometric analyses to identify covariates that explain between-subject variability (BSV) in exposure and exposure –response relationships. However, this approach has several potential weaknesses, including over-estimated covariate effect and incorrect selection of covariates due to collinearity. In this work, we investigated the operating characteristics (i.e., accuracy, precision, and power) of SCM in a cont rolled setting by simulating sixteen scenarios with up to four covariate relationships. The SCM analysis showed a decrease in the power to ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 23, 2019 Category: Drugs & Pharmacology Source Type: research

Pitfalls of using numerical predictive checks for population physiologically-based pharmacokinetic model evaluation
AbstractComparisons between observed data and model simulations represent a critical component for establishing confidence in population physiologically-based pharmacokinetic (Pop-PBPK) models. Numerical predictive checks (NPC) that assess the proportion of observed data that correspond to Pop-PBPK model prediction intervals (PIs) are frequently used to qualify such models. We evaluated the effects of three components on the performance of NPC for qualifying Pop-PBPK model concentration –time predictions: (1) correlations (multiple samples per subject), (2) residual error, and (3) discrepancies in the distribution of...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 22, 2019 Category: Drugs & Pharmacology Source Type: research

Reproducible pharmacokinetics
AbstractReproducibility is a highly desired feature of scientific investigation in general, and it has special connotations for research in pharmacokinetics, a vibrant field with over 500,000 publications to-date. It is important to be able to differentiate between genuine heterogeneity in pharmacokinetic parameters from heterogeneity that is due to errors and biases. This overview discusses efforts and opportunities to diminish the latter type of undesirable heterogeneity. Several reporting and research guidance documents and standards have been proposed for pharmacokinetic studies, but their adoption is still rather limi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 18, 2019 Category: Drugs & Pharmacology Source Type: research

Development of visual predictive checks accounting for multimodal parameter distributions in mixture models
AbstractThe assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an indi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 8, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis
This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0 –0.5, 0.5–2, 2–4 and 4–6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment mo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 7, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic reanalysis of a Diazepam PBPK model: a comparison of Stan and GNU MCSim
AbstractThe aim of this study is to benchmark two Bayesian software tools, namelyStan andGNU MCSim, that use different Markov chain Monte Carlo (MCMC) methods for the estimation of physiologically based pharmacokinetic (PBPK) model parameters. The software tools were applied and compared on the problem of updating the parameters of a Diazepam PBPK model, using time-concentration human data. Both tools produced very good fits at the individual and population levels, despite the fact thatGNU MCSim is not able to consider multivariate distributions.Stan outperformedGNU MCSim in sampling efficiency, due to its almost uncorrela...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 3, 2019 Category: Drugs & Pharmacology Source Type: research

Estimating parameters of nonlinear dynamic systems in pharmacology using chaos synchronization and grid search
AbstractBridging 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 and grid search to estimate physiological and pharmacological systems with emergent properties by exploring deterministic methods that are more appropriate and have potentially superior performance than classical numerical approaches, which minimize the sum of squares or maximize the likelihood. We il...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 29, 2019 Category: Drugs & Pharmacology Source Type: research

Preface to Special Issue for Panos Macheras
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 29, 2019 Category: Drugs & Pharmacology Source Type: research

Panos Macheras: a pioneering scientist in pharmaceutical science
AbstractProfessor Panos Macheras is a pioneering scientist in pharmacokinetics, pharmacodynamics and biopharmaceutics. His many important contributions to pharmaceutical science are reviewed. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 27, 2019 Category: Drugs & Pharmacology Source Type: research

Understanding drug –drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs
AbstractHere we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug –drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration–time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-l ife. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interac...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 24, 2019 Category: Drugs & Pharmacology Source Type: research

Accounting for inter-correlation between enzyme abundance: a simulation study to assess implications on global sensitivity analysis within physiologically-based pharmacokinetics
AbstractPhysiologically based pharmacokinetic (PBPK) models often include several sets of correlated parameters, such as organ volumes and blood flows. Because of recent advances in proteomics, it has been demonstrated that correlations are also present between abundances of drug-metabolising enzymes in the liver. As the focus of population PBPK has shifted the emphasis from the average individual to theoretically conceivable extremes, reliable estimation of the extreme cases has become paramount. We performed a simulation study to assess the impact of the correlation between the abundances of two enzymes on the pharmacoki...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 22, 2019 Category: Drugs & Pharmacology Source Type: research

Structural identifiability and sensitivity
AbstractOrdinary 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 identifiable with the given set of inputs and outputs. The local identifiability of linear and nonlinear models was investigated by an approach based on the rank of the sensitivity matrix of model output with respect to parameters. Associated with multiple random drawn of parameters used as nominal valu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 19, 2019 Category: Drugs & Pharmacology Source Type: research

Monte Carlo simulations in drug release
We describe methods that have proven to be effective in illuminating the profound effects of the substrate heterogeneity on the drug release profiles and demonstrate some of the most powerful applications of agent based simulations and numerical methods in the field of pharmacokinetics. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 17, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics of inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma
AbstractThis population pharmacokinetics analysis evaluated the target-mediated drug disposition of inotuzumab ozogamicin (InO) through an empirical time-dependent clearance (CLt) term and identified potential covariates that may be important predictors of variability in InO distribution and elimination. This analysis was conducted by pooling data from 2 studies of single-agent InO in patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL), 3 studies of single-agent InO, 5 studies of InO plus rituximab (R-InO), and 1 study of R-InO plus chemotherapy in patients with R/R B-cell non-Hodgkin lymph...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 10, 2019 Category: Drugs & Pharmacology Source Type: research

Bioequivalence for highly variable drugs: regulatory agreements, disagreements, and harmonization
AbstractRegulatory authorities introduced procedures in the last decade for evaluating the bioequivalence (BE) for highly variable drugs. These approaches are similar in principle but differ in details. For example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend differing regulatory constants. The constant suggested by FDA results in discontinuity of the BE limits around the switching variation at 30% observed within-subject variation of the reference product. The regulatory constant of EMA does not have these problems. The Type I error reaches 6 –7% around the switching vari...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 23, 2019 Category: Drugs & Pharmacology Source Type: research

Challenge model of TNF α turnover at varying LPS and drug provocations
AbstractA mechanism-based biomarker model of TNFα-response, including different external provocations of LPS challenge and test compound intervention, was developed. The model contained system properties (such askt, kout), challenge characteristics (such asks, kLPS, Km,  LPS, Smax, SC50) and test-compound-related parameters (Imax, IC50). The exposure to test compound was modelled by means of first-order input and Michaelis –Menten type of nonlinear elimination. Test compound potency was estimated to 20 nM with a 70% partial reduction in TNFα-response at the highest dose of 30  mg·kg&...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 18, 2019 Category: Drugs & Pharmacology Source Type: research

Application of new measures of nonlinearity to parameter estimation and simulations in individual pharmacokinetic analyses
AbstractSince simulation studies are widely used in pharmacokinetics, it is necessary to ascertain their validity. An important, well-documented, concern that may negatively impact the validity of estimated parameters in pharmacokinetic models is existence of multiple minima of the criterion used in estimation. A presence of multiple minima causes instability of the estimates, dependence of the parameter estimates on the initial values, and bimodal (or, generally, multimodal) distributions of the estimated parameters. This paper offers a method to identify when these issues may occur by applying two new measures of nonline...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 1, 2019 Category: Drugs & Pharmacology Source Type: research

Indirect pharmacodynamic models for responses with circadian removal
AbstractRhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate\( k_{in} \left( t \right) \) or a periodic time-dependent loss constant\( k_{out} \left( t \right) \). If either\( k_{in} \left( t \right) \) or\( k_{out} \left( t \right) \) follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates\( \left[ {k_{in} \left( t \right)} \right] \) have been utilized to capture drug effects on various physiolo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 29, 2019 Category: Drugs & Pharmacology Source Type: research

Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols
This study uses a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to analyse the oscillatory cortisol response and its interaction with dexamethasone. Two existing DST protocols were then scrutinized using model simulations with particular focus on their ability to avoid false positive outcomes. Using a Bayesian population approach allowed for quantification of uncertainty and enabled predictions for a broader population of horses than the underlying sample. Dose selection and sampling time point were both determined to have large influence on the number of false positives. Advice on pitfalls in test protocols a...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 23, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch
AbstractDanvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4  mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 19, 2019 Category: Drugs & Pharmacology Source Type: research

Ordinary differential equation approximation of gamma distributed delay model
AbstractIn many models of pharmacodynamic systems with delays, a delay of an input is introduced by means of the convolution with the gamma distribution. An approximation of the convolution integral of bound functions based on a system of ordinary differential equations that utilizes properties of the binomial series has been introduced. The approximation converges uniformly on every compact time interval and an estimate of the approximation error has been found\(O\left( {\frac{1}{{N^{\nu } }}} \right)\) where\(N\) is the number of differential equations and\(\nu\) is the shape parameter of the gamma distribution. The accu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 7, 2019 Category: Drugs & Pharmacology Source Type: research

Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I –IV drugs
AbstractRegulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 14, 2018 Category: Drugs & Pharmacology Source Type: research

Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling
This study illustrates application of QSP modeling to predict phase II endpoints from phase I data. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 16, 2018 Category: Drugs & Pharmacology Source Type: research

Development of a nonlinear hierarchical model to describe the disposition of deuterium in mother –infant pairs to assess exclusive breastfeeding practice
AbstractThe World Health Organization recommends exclusive breastfeeding (EBF) for the first 6  months after birth. The deuterium oxide dose-to-the-mother (DTM) technique is used to distinguish EBF based on a cut-off (
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 14, 2018 Category: Drugs & Pharmacology Source Type: research

MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues
In conclusion, this work provides a theoretical framework for the assessment of key properties of mathematical models before their experimental application. Attention should be paid when applying integrated mPBPK-TMDD models, as identifiability issues do exist, especially when rich study designs are not feasible. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 10, 2018 Category: Drugs & Pharmacology Source Type: research

Modeling the acute effects of exercise on insulin kinetics in type 1 diabetes
AbstractOur objective is to develop a physiology-based model of insulin kinetics to understand how exercise alters insulin concentrations in those with type 1 diabetes (T1D). We reveal the relationship between the insulin absorption rate (\(k^I_a\)) from subcutaneous tissue, the insulin delivery rate (\(k^I_d\)) to skeletal muscle, and two physiological parameters that characterize the tissue: the perfusion rate (Q) and the capillary permeability surface area (PS), both of which increase during exercise because of capillary recruitment. We compare model predictions to experimental observations from two pump-wearing T1D coh...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 3, 2018 Category: Drugs & Pharmacology Source Type: research

Modeling near-continuous clinical endpoint as categorical: application to longitudinal exposure –response modeling of Mayo scores for golimumab in patients with ulcerative colitis
AbstractAccurate characterization of exposure –response relationship of clinical endpoints is important in drug development to identify optimal dose regimens. Endpoints with ≥ 10 ordered categories are typically analyzed as continuous. This manuscript aims to show circumstances where it is advantageous to analyze such data as ordered cate gorical. The results of continuous and categorical analyses are compared in a latent-variable based Indirect Response modeling framework for the longitudinal modeling of Mayo scores, ranging from 0 to 12, which is commonly used as a composite endpoint to measure the severi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 30, 2018 Category: Drugs & Pharmacology Source Type: research

A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans
AbstractBIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD. In particular, PK data from 17 cynomolgus monkeys were utilized for...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 30, 2018 Category: Drugs & Pharmacology Source Type: research

The use of PBPK modeling across the pediatric age range using propofol as a case
AbstractThe project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In t...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 8, 2018 Category: Drugs & Pharmacology Source Type: research

Joint longitudinal model development: application to exposure –response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with sirukumab
AbstractExposure –response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure–response modeling of sirukumab. Sirukumab is a human anti- interleukin-6 (IL-6) monoclonal antibody that ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

An item response theory based integrated model of headache, nausea, photophobia, and phonophobia in migraine patients
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 conducted during the development of eletriptan. Only the placebo arm was used for analysis. A conventional proportional odds model was compared with an item response theory (IRT) based approach. Results suggested that the IRT based approach led to a better model fit, successfully revealing the difference in reli...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research