Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale
AbstractL-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2 –5 years old accounting for enzyme m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Mathematical analysis and drug exposure evaluation of pharmacokinetic models with endogenous production and simultaneous first-order and Michaelis –Menten elimination: the case of single dose
AbstractDrugs with an additional endogenous source often exhibit simultaneous first-order and Michaelis –Menten elimination and are becoming quite common in pharmacokinetic modeling. In this paper, we investigate the case of single dose intravenous bolus administration for the one-compartment model. Relying on a formerly introduced transcendent function, we were able to analytically express the conc entration time course of this model and provide the pharmacokinetic interpretation of its components. Using the concept of the corrected concentration, the mathematical expressions for the partial and total areas under th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts
In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity. The network model developed for drug effects in the in vitro cell cultures was applied successfully to link the in vivo tumor drug concentration...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics –pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex
The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure fre quency and everolimus exposure to confirm the recommended target concentration range of 5–15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustmen ts. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Data standards for model-informed drug development: an ISoP initiative
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models
The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as “Springer Science+Business Media, LLC, part of Springer Nature 2018”. Instead, it should be “The Author(s) 2018”. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

The Ninth American Conference on Pharmacometrics (ACoP9)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 1, 2018 Category: Drugs & Pharmacology Source Type: research

Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale
AbstractL-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2 –5 years old accounting for enzyme m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2018 Category: Drugs & Pharmacology Source Type: research

Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 10, 2018 Category: Drugs & Pharmacology Source Type: research

The Ninth American Conference on Pharmacometrics (ACoP9)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 5, 2018 Category: Drugs & Pharmacology Source Type: research

Correction to: Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models
The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as “Springer Science+Business Media, LLC, part of Springer Nature 2018”. Instead, it should be “The Author(s) 2018”. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 31, 2018 Category: Drugs & Pharmacology Source Type: research

Projected 24-hour post-dose ocular itching scores post-treatment with olopatadine 0.7% versus 0.2%
The objective of this analysis was to characterize patients who have better itching relief at 24  h when taking olopatadine 0.7% treatment instead of olopatadine 0.2% (in terms of proportions of responses) and relate this to the severity of baseline itching as an indirect metric of a patient’s sensitivity to antihistamines. A differential odds model was developed using data from two conjunct ival allergen challenge (CAC) studies to characterize individual-level and population-level response to ocular itching following olopatadine treatment and the data was analyzed retrospectively. This modeling analysis was des...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Model reduction in mathematical pharmacology
AbstractIn this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models
AbstractDrug –target binding kinetics (as determined by association and dissociation rate constants,kon andkoff) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug –target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment–target binding kinetics (EC–TB) model were tested on either plasma (ECPL, TBPL and E...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model
AbstractMonoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

A comprehensive evaluation of exposure –response relationships in clinical trials: application to support guselkumab dose selection for patients with psoriasis
AbstractGuselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator ’s Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure–response (E–R) modeling analyses, we sought to predict the guselkumab dose–response (D–R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma
In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver
AbstractA multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBP β) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dyn...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics
The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol —Taxol®) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration –time data following single intravenous bolus administration of Taxol® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments. The final model resulted in a g...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures
AbstractModeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4 –17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2–18  years of age treated with ESL 5–30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (inclu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts
In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity. The network model developed for drug effects in the in vitro cell cultures was applied successfully to link the in vivo tumor drug concentration...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2018 Category: Drugs & Pharmacology Source Type: research

Data standards for model-informed drug development: an ISoP initiative
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 25, 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 - July 24, 2018 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics –pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex
The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure fre quency and everolimus exposure to confirm the recommended target concentration range of 5–15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustmen ts. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 10, 2018 Category: Drugs & Pharmacology Source Type: research

Mathematical analysis and drug exposure evaluation of pharmacokinetic models with endogenous production and simultaneous first-order and Michaelis –Menten elimination: the case of single dose
AbstractDrugs with an additional endogenous source often exhibit simultaneous first-order and Michaelis –Menten elimination and are becoming quite common in pharmacokinetic modeling. In this paper, we investigate the case of single dose intravenous bolus administration for the one-compartment model. Relying on a formerly introduced transcendent function, we were able to analytically express the conc entration time course of this model and provide the pharmacokinetic interpretation of its components. Using the concept of the corrected concentration, the mathematical expressions for the partial and total areas under th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 9, 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 - June 30, 2018 Category: Drugs & Pharmacology Source Type: research

Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals
AbstractThe physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite —nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. The cardiac effect with r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 25, 2018 Category: Drugs & Pharmacology Source Type: research

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures
AbstractModeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4 –17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2–18  years of age treated with ESL 5–30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (inclu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 9, 2018 Category: Drugs & Pharmacology Source Type: research

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model
AbstractMonoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 8, 2018 Category: Drugs & Pharmacology Source Type: research

Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models
AbstractDrug –target binding kinetics (as determined by association and dissociation rate constants,kon andkoff) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug –target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment–target binding kinetics (EC–TB) model were tested on either plasma (ECPL, TBPL and E...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 18, 2018 Category: Drugs & Pharmacology Source Type: research

A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation
AbstractDrugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 7, 2018 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics and exposure –response modeling and simulation for evolocumab in healthy volunteers and patients with hypercholesterolemia
AbstractEvolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure –response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7–420 mg at various frequencies, either intravenously or subcutaneously...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 7, 2018 Category: Drugs & Pharmacology Source Type: research

Multiscale systems pharmacological analysis of everolimus action in hepatocellular carcinoma
In conclusion, a multiscale QSP/PK/PD model elucidating everolimus lack of efficacy in HCC patients was successfully developed and predicted PFS reasonably well compared to observed clinical findings. This model may provide insights into clinical response to everolimus-based therapy and serve as a valuable tool for the clinical translation of efficacy for novel mTOR inhibitors. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 3, 2018 Category: Drugs & Pharmacology Source Type: research

Editorial to themed issue: Recent advances in cardiovascular pharmacokinetic –pharmacodynamic modeling and simulation
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 2, 2018 Category: Drugs & Pharmacology Source Type: research

Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver
AbstractA multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBP β) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dyn...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 27, 2018 Category: Drugs & Pharmacology Source Type: research

Projected 24-hour post-dose ocular itching scores post-treatment with olopatadine 0.7% versus 0.2%
The objective of this analysis was to characterize patients who have better itching relief at 24  h when taking olopatadine 0.7% treatment instead of olopatadine 0.2% (in terms of proportions of responses) and relate this to the severity of baseline itching as an indirect metric of a patient’s sensitivity to antihistamines. A differential odds model was developed using data from two conjunct ival allergen challenge (CAC) studies to characterize individual-level and population-level response to ocular itching following olopatadine treatment and the data was analyzed retrospectively. This modeling analysis was des...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 21, 2018 Category: Drugs & Pharmacology Source Type: research

Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics
The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol —Taxol®) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration –time data following single intravenous bolus administration of Taxol® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments. The final model resulted in a g...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 18, 2018 Category: Drugs & Pharmacology Source Type: research

Importance of QT/RR hysteresis correction in studies of drug-induced QTc interval changes
This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations. Statistical modeling approach was used to generate 11,000 simulated samples of 10-subject studies in which mixed effect PK/PD models were used to estimate drug-induced QTc changes at mean maximum plasma concentration of investigated compounds. Calculations of QTc intervals involving and omitting QT/RR hysteresis correction were compared. These comparisons showed that ignoring QT/RR hysteresis has two undesirable effe...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 12, 2018 Category: Drugs & Pharmacology Source Type: research

Model reduction in mathematical pharmacology
AbstractIn this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models. The overall methodology is demonstrated via two example systems; a model ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 26, 2018 Category: Drugs & Pharmacology Source Type: research

Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods
AbstractModeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C- ∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound , AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 19, 2018 Category: Drugs & Pharmacology Source Type: research

A comprehensive evaluation of exposure –response relationships in clinical trials: application to support guselkumab dose selection for patients with psoriasis
AbstractGuselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator ’s Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure–response (E–R) modeling analyses, we sought to predict the guselkumab dose–response (D–R) relationship using data from 1459 patients who participated in these trials. A recently developed novel latent-variable Type ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 16, 2018 Category: Drugs & Pharmacology Source Type: research

Drug –physiology interaction and its influence on the QT prolongation-mechanistic modeling study
AbstractThe current study is an example of drug –disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simu lator. Biophysically detailed model of the human cardiac physiology—ten Tusscher ventricular cardiomyocyte cell model—was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values wi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 15, 2018 Category: Drugs & Pharmacology Source Type: research

Quantitative approach for cardiac risk assessment and interpretation in tuberculosis drug development
AbstractCardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 8, 2018 Category: Drugs & Pharmacology Source Type: research

Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors
The objective of this study was  to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins i nvolved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems pharmacology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 14, 2018 Category: Drugs & Pharmacology Source Type: research

Correction to: PK –PD Compass: bringing infectious diseases pharmacometrics to the patient’s bedside
AbstractThe original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 14, 2018 Category: Drugs & Pharmacology Source Type: research

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data
AbstractAmiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants  
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2018 Category: Drugs & Pharmacology Source Type: research

Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression
In conclusion, the distributed delay model was deterministically identifiable from typical cytotoxic data. Its performance was modestly better than the classic model with significantly longer running time. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 12, 2018 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens
AbstractTrastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure –response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 10, 2018 Category: Drugs & Pharmacology Source Type: research

Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model
AbstractAmlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug –drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) mod...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 9, 2018 Category: Drugs & Pharmacology Source Type: research