Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model
AbstractASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this mode...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 15, 2020 Category: Drugs & Pharmacology Source Type: research

Mechanism-based modeling of the effect of a novel inhibitor of vascular adhesion protein-1 on albuminuria and renal function markers in patients with diabetic kidney disease
AbstractThe vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12  weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated mann er. Drug-inde...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2020 Category: Drugs & Pharmacology Source Type: research

Diffusion through skin in the light of a fractional derivative approach: progress and challenges
AbstractThis review is focussed on modelling the transport processes of different drugs across the intact human skin by introducing a memory formalism based on the fractional derivative approach. The fundamental assumption of the classic transport equation in the light of the Fick ’s law is that the skin barrier behaves as a pseudo-homogeneous membrane and that its properties, summarized by the diffusion coefficientD,   do not vary with time and position. This assumption does not hold in the case of a highly heterogeneous system as the skin is, whose outermost layer (the stratum corneum) is comprised of a multi-...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2020 Category: Drugs & Pharmacology Source Type: research

Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits
AbstractDevelopment of protein therapeutics for ocular disorders, particularly age-related macular degeneration (AMD), is a highly competitive and expanding therapeutic area. However, the application of a predictive and translatable ocular PK model to better understand ocular disposition of protein therapeutics, such as a physiologically-based pharmacokinetic (PBPK) model, is missing from the literature. Here, we present an expansion of an antibody platform PBPK model towards rabbit and incorporate a novel anatomical and physiologically relevant ocular component. Parameters describing all tissues, flows, and binding events...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 2, 2020 Category: Drugs & Pharmacology Source Type: research

Longitudinal analysis of organ-specific tumor lesion sizes in metastatic colorectal cancer patients receiving first line standard chemotherapy in combination with anti-angiogenic treatment
AbstractThe purpose of this work is to assess the heterogeneity across organs of response to treatment in metastatic colorectal patient based on longitudinal individual target lesion diameters (ILD) in comparison to sum of tumor lesion diameters (SLD). Data were from the McCAVE trial, in which 189 previously untreated patients with metastatic colorectal carcinoma (mCRC) received either bevacizumab (control, C) or vanucizumab (experimental, E), on top of standard chemotherapy. Bayesian hierarchical longitudinal non-linear mixed effect models were fitted to the data using Hamilton Monte Carlo algorithm to characterize the ti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 31, 2020 Category: Drugs & Pharmacology Source Type: research

The influence of cardiac output on propofol and fentanyl pharmacokinetics and pharmacodynamics in patients undergoing abdominal aortic surgery
AbstractCardiac output (CO) is expected to affect elimination and distribution of highly extracted and perfusion rate-limited drugs. This work was undertaken to quantify the effect of CO measured by the pulse pressure method on pharmacokinetics and pharmacodynamics of propofol and fentanyl administrated during total intravenous anesthesia (TIVA). The data were obtained from 22 ASA III patients undergoing abdominal aortic surgery. Propofol was administered via target-controlled infusion system (Diprifusor) and fentanyl was administered at a dose of 2 –3 µg/kg each time analgesia appeared to be inadequate. H...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 25, 2020 Category: Drugs & Pharmacology Source Type: research

Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy
This study aimed at predicting maternal drug kinetics using a physiologically based pharmacokinetic (PBPK) modelling approach focusing on the observed gestational changes in three important Cytochrome P450 metabolizing enzymes, namely, CYP1A2, CYP2D6 and CYP3A4 at different gestational weeks (GWs). The Pregnancy PBPK model within the Simcyp Simulator V19 was used to predict the pharmacokinetics of sensitive probes to these enzymes; namely caffeine, theophylline, metoprolol, propranolol, paroxetine, midazolam, nifedipine and rilpivirine. PBPK model predictions were compared against clinical data collated from multiple studi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 25, 2020 Category: Drugs & Pharmacology Source Type: research

Bolus pharmacokinetics: moving beyond mass-based dosing to guide drug administration
AbstractDespite the common approach of bolus drug dosing using a patient ’s mass, a more tailored approach would be to use empirically derived pharmacokinetic models. Previously, this could only be possible though the use of computer simulation using programs which are rarely available in clinical practice. Through mathematical manipulations and approximations, a simpl ified set of equations is demonstrated that can identify a bolus dose required to achieve a specified target effect site concentration. The proposed solution is compared against simulations of a wide variety of pharmacokinetic models. This set of equat...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 18, 2020 Category: Drugs & Pharmacology Source Type: research

A pharmacometrician ’s role in enhancing medication use in pregnancy and lactation
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 16, 2020 Category: Drugs & Pharmacology Source Type: research

Composite midazolam and 1 ′-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity
The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1 ′-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 8, 2020 Category: Drugs & Pharmacology Source Type: research

Application of Brunauer –Emmett–Teller (BET) theory and the Guggenheim–Anderson–de Boer (GAB) equation for concentration-dependent, non-saturable cell–cell interaction dose-responses
AbstractTo systematically assess the characteristics and potential utility of the Guggenheim –Anderson–de Boer (GAB) formulation of the Brunauer–Emmett–Teller (BET) equation from physical chemistry for modeling dose-responses in pharmaceutical applications. The GAB–BET equation was derived using pharmacodynamic first principles to underscore the assumptions involved and the functi onal characteristics of the equation were investigated. The properties of the GAB–BET equation were compared to the familiar Michaelis–Menten and Hill equations and its utility for pharmacokinetic-pharmac...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 8, 2020 Category: Drugs & Pharmacology Source Type: research

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 3, 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 31, 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 24, 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 24, 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 13, 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 9, 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 2, 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 26, 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 22, 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 13, 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 4, 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 2, 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 - June 1, 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 29, 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 20, 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 13, 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 25, 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 22, 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 18, 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 13, 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 11, 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 4, 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 4, 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 26, 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 11, 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 25, 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 17, 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 11, 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 7, 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 6, 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 4, 2020 Category: Drugs & Pharmacology Source Type: research

The guard changes
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 28, 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 22, 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 20, 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 20, 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 14, 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 6, 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 3, 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 21, 2019 Category: Drugs & Pharmacology Source Type: research