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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

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 - 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 - 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