Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery
The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound (\({f}_{u}\)) of predominantly albumin-bound drugs was predicted in postpartum women ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 2, 2020 Category: Drugs & Pharmacology Source Type: research

Well-tempered MCMC simulations for population pharmacokinetic models
AbstractA full Bayesian statistical treatment of complex pharmacokinetic or pharmacodynamic models, in particular in a population context, gives access to powerful inference, including on model structure. Markov Chain Monte Carlo (MCMC) samplers are typically used to estimate the joint posterior parameter distribution of interest. Among MCMC samplers, the simulated tempering algorithm (TMCMC) has a number of advantages: it can sample from sharp multi-modal posteriors; it provides insight into identifiability issues useful for model simplification; it can be used to compute accurate Bayes factors for model choice; the simul...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 30, 2020 Category: Drugs & Pharmacology Source Type: research

Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1
In conclusion, a fit-for-purpose translational PK/PD strategy for ADCs is presented and used to compare a new generation HER2 ADC with T-DM1. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2020 Category: Drugs & Pharmacology Source Type: research

PBPK modeling of CYP3A and P-gp substrates to predict drug –drug interactions in patients undergoing Roux-en-Y gastric bypass surgery
AbstractRoux-en-Y gastric bypass surgery (RYGBS) is an effective surgical intervention to reduce mortality in morbidly obese patients. Following RYGBS, the disposition of drugs may be affected by anatomical alterations and changes in intestinal and hepatic drug metabolizing enzyme activity. The aim of this study was to better understand the drug –drug interaction (DDI) potential of CYP3A and P-gp inhibitors. The impacts of RYGBS on the absorption and metabolism of midazolam, acetaminophen, digoxin, and their major metabolites were simulated using physiologically-based pharmacokinetic (PBPK) modeling. PBPK models for ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 23, 2020 Category: Drugs & Pharmacology Source Type: research

Comparison of covariate selection methods with correlated covariates: prior information versus data information, or a mixture of both?
AbstractThe inclusion of covariates in population models during drug development is a key step to understanding drug variability and support dosage regimen proposal, but high correlation among covariates often complicates the identification of the true covariate. We compared three covariate selection methods balancing data information and prior knowledge: (1) full fixed effect modelling (FFEM), with covariate selection prior to data analysis, (2) simplified stepwise covariate modelling (sSCM), data driven selection only, and (3) Prior-Adjusted Covariate Selection (PACS) mixing both. PACS penalizes the a priori less likely ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 12, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor
AbstractTo develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N  = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteopor...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 8, 2020 Category: Drugs & Pharmacology Source Type: research

Performance of longitudinal item response theory models in shortened or partial assessments
AbstractThis work evaluates the performance of longitudinal item response (IR) theory models in shortened assessments using an existing model for part II and III of the MDS-UPDRS score. Based on the item information content, the assessment was reduced by removal of items in multiple increments and the models ’ ability to recover the item characteristics of the remaining items at each level was evaluated. This evaluation was done for both simulated and real data. The metric of comparison in both cases was the item information function. For real data, the impact of shortening on the estimated disease pr ogression and d...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 1, 2020 Category: Drugs & Pharmacology Source Type: research

Drug dosing during pregnancy —opportunities for physiologically based pharmacokinetic models
AbstractDrugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendati...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 25, 2020 Category: Drugs & Pharmacology Source Type: research

PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration
AbstractPlasma drug concentration and electrocardiogram (ECG) data from a drug –drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were colle cted on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both “therapeutic” and “supra-therapeut...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 21, 2020 Category: Drugs & Pharmacology Source Type: research

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine
AbstractPopulation pharmacokinetic analysis is used to estimate pharmacokinetic parameters and their variability from concentration data. Due to data sparseness issues, available datasets often do not allow the estimation of all parameters of the suitable model. The PRIOR subroutine in NONMEM supports the estimation of some or all parameters with values from previous models, as an alternative to fixing them or adding data to the dataset. From a literature review, the best practices were compiled to provide a practical guidance for the use of the PRIOR subroutine in NONMEM. Thirty-three articles reported the use of the PRIO...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 12, 2020 Category: Drugs & Pharmacology Source Type: research

Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling
AbstractUse of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because of an incomplete understanding of fundamental mechanisms controlling mAb absorption from the SC site, and due to the limited translatability of preclinical studies. In this paper, we report on the development and evaluation of a whole-body physiologically-based model to predict mAb pharmacokinetics following SC administration. The circulatory model is based on the physiological processes governing mAb transport and includes two mAb-specific parameters representing differences in pi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 3, 2020 Category: Drugs & Pharmacology Source Type: research

Target-mediated exposure enhancement: a previously unexplored limit of TMDD
AbstractTarget-mediated drug disposition (TMDD) is often observed for targeted therapeutics, and manifests as decreases in clearance and volume of distribution with increasing dose as a result of saturable, high affinity target binding. In the present work, we demonstrate that classically defined TMDD is just one of the characteristic features of the system. In fact, for molecules with rapid non-specific elimination relative to target-mediated elimination, binding to target may actually lead to improved exposure at sub-saturating doses. This feature, which we refer to as target-mediated exposure enhancement (TMEE), produce...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 1, 2020 Category: Drugs & Pharmacology Source Type: research

A model-based analysis identifies differences in phenotypic resistance between in vitro and in vivo: implications for translational medicine within tuberculosis
AbstractProper characterization of drug effects onMycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure –response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of i n vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated base...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 31, 2020 Category: Drugs & Pharmacology Source Type: research

Musings on the current state of COVID-19 modeling and reporting
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 28, 2020 Category: Drugs & Pharmacology Source Type: research

Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2
AbstractTo face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to charact...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 19, 2020 Category: Drugs & Pharmacology Source Type: research

Hydroxychloroquine and azithromycin as potential treatments for COVID-19; clinical status impacts the outcome
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 12, 2020 Category: Drugs & Pharmacology Source Type: research

A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus
AbstractA population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n  = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 24, 2020 Category: Drugs & Pharmacology Source Type: research

Use of normalized prediction distribution errors for assessing population physiologically-based pharmacokinetic model adequacy
In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution err ors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and nega...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 21, 2020 Category: Drugs & Pharmacology Source Type: research

Challenges in conducting clinical research studies in pregnant women
This article provides an overview of issues surrounding inclusion of pregnant or breastfeeding women in research studies, and includes historical perspectives, navigating concerns over safety profile, considerations for appropriate development, and future perspectives. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 17, 2020 Category: Drugs & Pharmacology Source Type: research

A longitudinal item response model for Aberrant Behavior Checklist (ABC) data from children with autism
AbstractThis manuscript aims to present the first item response theory (IRT) model within a pharmacometric framework to characterize the longitudinal changes of Aberrant Behavior Checklist (ABC) data in children with autism. Data were obtained from 120 patients, which included 20,880 observations of the 58 items for up to three months. Observed scores for each ABC item were modeled as a function of the subject's disability. Longitudinal IRT models with five latent disability variables based on ABC subscales were used to describe the irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech over ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 12, 2020 Category: Drugs & Pharmacology Source Type: research

Enabling pregnant women and their physicians to make informed medication decisions using artificial intelligence
AbstractThe role of artificial intelligence (AI) in healthcare for pregnant women. To assess the role of AI in women ’s health, discover gaps, and discuss the future of AI in maternal health. A systematic review of English articles using EMBASE, PubMed, and SCOPUS. Search terms included pregnancy and AI. Research articles and book chapters were included, while conference papers, editorials and notes were exclude d from the review. Included papers focused on pregnancy and AI methods, and pertained to pharmacologic interventions. We identified 376 distinct studies from our queries. A final set of 31 papers were include...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 10, 2020 Category: Drugs & Pharmacology Source Type: research

Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling
This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions o f BIM23B065. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 3, 2020 Category: Drugs & Pharmacology Source Type: research

Assessing parameter uncertainty in small-n pharmacometric analyses: value of the log-likelihood profiling-based sampling importance resampling (LLP-SIR) technique
AbstractAssessing parameter uncertainty is a crucial step in pharmacometric workflows. Small datasets with ten or fewer subjects appear regularly in drug development and therapeutic use, but it is unclear which method to assess parameter uncertainty is preferable in such situations. The aim of this study was to (i) systematically evaluate the performance of standard error (SE), bootstrap (BS), log-likelihood profiling (LLP), Bayesian approaches (BAY) and sampling importance resampling (SIR) to assess parameter uncertainty in small datasets and (ii) to evaluate methods to provide proposal distributions for the SIR. A simula...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 3, 2020 Category: Drugs & Pharmacology Source Type: research

COVID-19: opportunity arises from a world health crisis
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 25, 2020 Category: Drugs & Pharmacology Source Type: research

A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor
AbstractNeutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinet...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 10, 2020 Category: Drugs & Pharmacology Source Type: research

Age progression from vicenarians (20 –29 year) to nonagenarians (90–99 year) among a population pharmacokinetic/pharmacodynamic (PopPk-PD) covariate analysis of propofol-bispectral index (BIS) electroencephalography
ConclusionWe quantified and graded EEG-BIS age-progression among different age groups divided by decades. We demonstrated deeper BIS values with decades ’ age progression. Our data has important implications for propofol dosing. The practical information for physicians in their daily clinical practice is using propofol Cp of 3.5  μg mL−1 might not yield BIS value of 50 in elderly patients. Our simulations showed that the recommended regimen of Cp 3.5  μg mL−1 for 20 –29 year should be gradually decreased to 2.0 μg mL−1 for 80 –89 year.Clin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 24, 2020 Category: Drugs & Pharmacology Source Type: research

Thanks to Our Reviewers 2019!
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 16, 2020 Category: Drugs & Pharmacology Source Type: research

A time-to-event analysis of the exposure –response relationship for bezlotoxumab concentrations and CDI recurrence
AbstractBezlotoxumab is a monoclonal antibody approved for the prevention of recurrentClostridium difficile infection (rCDI). In a previous exposure –response (E–R) analysis of bezlotoxumab exposure and rCDI, based on data from two phase 3 trials in participants who received placebo or bezlotoxumab 10 mg/kg, rCDI was treated as a binary endpoint and discontinued subjects were imputed as not having rCDI, resulting in an apparent positive E– R trend between rCDI rates and bezlotoxumab exposure. Therefore, a time-to-event (TTE) analysis was applied to investigate the E–R relationship, accounting f...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 10, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical lactation studies and the role of pharmacokinetic modeling and simulation in predicting drug exposures in breastfed infants
AbstractThe relative lack of information on medication use during breastfeeding is an ongoing problem for health professionals and mothers alike. Most nursing mothers are prescribed some form of medication, yet some mothers either discontinue breastfeeding or avoid medications entirely. Although regulatory authorities have proposed a framework for clinical lactation studies, data on drug passage into breastmilk are often lacking. Model-based approaches can potentially be used to estimate the passage of drugs into milk, predict exposures in breastfed infants, and identify drugs that need clinical lactation studies. When a h...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 6, 2020 Category: Drugs & Pharmacology Source Type: research

Anatomical and physiological alterations of pregnancy
AbstractThe extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the te...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 5, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and pharmacodynamics of three oral formulations of curcumin in rats
AbstractCurcumin (CUR) is a major component of turmericCurcuma longa, which is often used in food or as a dietary supplement. The purpose of this preclinical study is to investigate the acute pharmacokinetic and pharmacodynamic (PK/PD) profiles of two commercially marketed CUR products (GNC and Vitamin Shoppe) and a CUR powder from Sigma in female rats. Plasma samples were collected at specific time points and analyzed for CUR and its metabolite curcumin-O-glucuronide. RNA was extracted from leukocytes and analyzed for the expression of Nrf2-mediated antioxidant genes Nrf2, Ho-1, and Nqo1 by qPCR as selected PD markers. CU...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 3, 2020 Category: Drugs & Pharmacology Source Type: research

The guard changes
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

Disease progression model of 4T1 metastatic breast cancer
This study provides a comprehensive description of lung metastasis progression for 4T1 breast cancer model, as well as an alternative disease progression model structure for further pharmacodynamics modeling. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 21, 2020 Category: Drugs & Pharmacology Source Type: research

Latent process model of the 6-minute walk test in Duchenne muscular dystrophy
The objective of this study was to enhance the quantitative understanding of DMD disease progression through nonlinear mixed effects modeling of the population mean and variability of the 6-min walk test (6MWT) clinical endpoint. An indirect response model with a latent process was fit to digitized literature data using full Bayesian estimation. The modeling data set consisted of 22 healthy controls and 218 DMD patients from one interventional and four observational trials. The model reasonably described the central tendency and population variability of the 6MWT in healthy subjects and DMD patients. An exploratory categor...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 19, 2020 Category: Drugs & Pharmacology Source Type: research

On the shoulders of giants …
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 19, 2020 Category: Drugs & Pharmacology Source Type: research

Population-based meta-analysis of bortezomib exposure –response relationships in multiple myeloma patients
In conclusion, a pharmacodynamic model was successfully developed, which provides a quantitative, mechanism-based platform for probing bortezomib dosing-regimens. Further research is needed t o determine whether this model could be used to individualize bortezomib regimens to maximize antineoplastic efficacy and minimize thrombocytopenia during MM treatment. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 13, 2020 Category: Drugs & Pharmacology Source Type: research

Evaluation of non-linear-mixed-effect modeling to reduce the sample sizes of pediatric trials in type 2 diabetes mellitus
AbstractRecruitment for pediatric trials in Type II Diabetes Mellitus (T2DM) is very challenging, necessitating the exploration of new approaches for reducing the sample sizes of pediatric trials. This work aimed at assessing if a longitudinal Non-Linear-Mixed-Effect (NLME) analysis of T2DM trial could be more powerful and thus require fewer patients than two standard statistical analyses commonly used as primary or sensitivity efficacy analysis: Last-Observation-Carried-Forward (LOCF) followed by (co)variance (AN(C)OVA) analysis at the evaluation time-point, and Mixed-effects Model Repeated Measures (MMRM) analysis. Stand...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 5, 2020 Category: Drugs & Pharmacology Source Type: research

The non-compartmental steady-state volume of distribution revisited
AbstractThe lack in the literature of a simple, yet general and complete derivation of the widely used equation for non-compartmental calculation of steady-state volume of distribution is pointed out. It is demonstrated that the most frequently cited references contain an overly simplified explanation. The logical gap consists in doubly defining the same quantities without a proof the definitions are equivalent. Two alternative solutions are proposed: analytical derivation and hydrodynamic analogy. It is shown, that the problem can be analyzed in a purely macroscopic framework by utilizing the integral mean value  of ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 2, 2020 Category: Drugs & Pharmacology Source Type: research

Comparison of the gamma-Pareto convolution with conventional methods of characterising metformin pharmacokinetics in dogs
AbstractA model was developed for long term metformin tissue retention based upon temporally inclusive models of serum/plasma concentration (\( C \)) having power function tails called the gamma-Pareto type I convolution (GPC) model and was contrasted with biexponential (E2) and noncompartmental (NC) metformin models. GPC models of\( C \) have a peripheral venous first arrival of drug-times parameter, early\( C \) peaks and very slow washouts of\( C \). The GPC, E2 and NC models were applied to a total of 148 serum samples drawn from 20 min to 72 h following bolus intravenous metformin in seven healthy mongrel dogs. The GP...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 20, 2019 Category: Drugs & Pharmacology Source Type: research

Optimization of clinical dosing schedule to manage neutropenia: learnings from semi-mechanistic modeling simulation approach
AbstractNeutropenia is a common side-effect of oncology drugs. We aimed to study the impact of exposure and dosing schedule on neutropenia to guide selection of dosing schedules that minimize neutropenia potential while maintaining the desired minimum concentration (Cmin) required for target engagement. Dose, frequency and PK parameters were chosen for five hypothetical drugs of various half-lives to (1) achieve same exposure with continuous dosing and evaluate impact of 4 intermittent dosing schedules; and (2) achieve same nadir for continuous and intermittent dosing and evaluate impact on% time above Cmin, a surrogate as...
Source: Journal of Pharmacokinetics and Pharmacodynamics - December 17, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Bayesian approach to investigate a two-state mixed model of COPD exacerbations
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

Journal editor ’s final report
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 12, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics and covariate analysis of Sym004, an antibody mixture against the epidermal growth factor receptor, in subjects with metastatic colorectal cancer and other solid tumors
AbstractSym004 is an equimolar mixture of two monoclonal antibodies, futuximab and modotuximab, which non-competitively block the epidermal growth factor receptor (EGFR). Sym004 has been clinically tested for treatment of solid tumors. The present work characterizes the non-linear pharmacokinetics (PK) of Sym004 and its constituent antibodies and investigates two types of covariate models for interpreting the interindividual variability of Sym004 exposure. Sym004 serum concentration data from 330 cancer patients participating in four Phase 1 and 2 trials (n  = 247 metastatic colorectal cancer, n =&thin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 1, 2019 Category: Drugs & Pharmacology Source Type: research

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates
AbstractCardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection –union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a th...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 29, 2019 Category: Drugs & Pharmacology Source Type: research

Impact of Phase 1 study design on estimation of QT interval prolongation risk using exposure –response analysis
AbstractThe International Council for Harmonisation (ICH) guidelines have been revised allowing for modeling of concentration-QT (C-QT) data from Phase I dose-escalation studies to be used as primary analysis for QT prolongation risk assessment of new drugs. This work compares three commonly used Phase I dose-escalation study designs regarding their efficiency to accurately identify drug effects on QT interval through C-QT modeling. Parallel group design and 4-period crossover designs with sequential or interleaving cohorts were evaluated. Clinical trial simulations were performed for each design and across different scena...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 28, 2019 Category: Drugs & Pharmacology Source Type: research

Handling underlying discrete variables with bivariate mixed hidden Markov models in NONMEM
AbstractNon-linear mixed effects models typically deal with stochasticity in observed processes but models accounting for only observed processes may not be the most appropriate for all data. Hidden Markov models (HMMs) characterize the relationship between observed and hidden variables where the hidden variables can represent an underlying and unmeasurable disease status for example. Adding stochasticity to HMMs results in mixed HMMs (MHMMs) which potentially allow for the characterization of variability in unobservable processes. Further, HMMs can be extended to include more than one observation source and are then multi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 25, 2019 Category: Drugs & Pharmacology Source Type: research

Cabozantinib exposure –response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma
AbstractCabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60  mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure–response (ER) models were developed to characterize ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 20, 2019 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis
AbstractThe ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure –response–outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 3, 2019 Category: Drugs & Pharmacology Source Type: research

Mathematical modeling of the glucagon challenge test
AbstractA model for the homeostasis of glucose through the regulating hormones glucagon and insulin is described. It contains a subsystem that models the internalization of the glucagon receptor. Internalization is a mechanism in cell signaling, through which G-protein coupled receptors are taken from the surface of the cell to the endosome. The model is used to interpret data from a glucagon challenge test in which subjects have been under treatment with a novel glucagon receptor anti-sense drug which is aimed at reducing the number of receptors in the liver. It is shown how the receptor internalization results in toleran...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 29, 2019 Category: Drugs & Pharmacology Source Type: research

Editorial to the themed issue on application of pharmacometrics to the development of drugs for rare diseases
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 26, 2019 Category: Drugs & Pharmacology Source Type: research