Modeling the acute effects of exercise on glucose dynamics in healthy nondiabetic subjects
AbstractTo shed light on how acute exercise affects blood glucose (BG) concentrations in nondiabetic subjects, we develop a physiological pharmacokinetic/pharmacodynamic model of postprandial glucose dynamics during exercise. We unify several concepts of exercise physiology to derive amultiscale model that includes three important effects of exercise on glucose dynamics: increased endogenous glucose production (EGP), increased glucose uptake in skeletal muscle (SM), and increased glucose delivery to SM by capillary recruitment (i.e. an increase in surface area and blood flow in capillary beds). We compare simulations to ex...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 4, 2021 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic modeling of intramuscular and oral dexamethasone and betamethasone in Indian women
AbstractPopulation analysis of pharmacokinetic data for five differing dosage forms and routes for dexamethasone and betamethasone in 48 healthy nonpregnant Indian women was performed that accounted for a partial and complex cross-over design. Single doses of 6  mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM). Plasma concentrations collected for two periods over 96 h were described with a two-compartment model with dif fering PO and IM first-order absorption inputs. Clearances ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 3, 2021 Category: Drugs & Pharmacology Source Type: research

A quantitative systems pharmacological approach identified activation of JNK signaling pathway as a promising treatment strategy for refractory HER2 positive breast cancer
AbstractHER2-positive breast cancer (BC) is a rapidly growing and aggressive  BC subtype that predominantly affects younger women. Despite improvements in patient outcomes with anti-HER2 therapy, primary and/or acquired resistance remain a major clinical challenge. Here, we sought to use a quantitative systems pharmacological (QSP) approach to evaluate the efficacy of lapa tinib (LAP), abemaciclib (ABE) and 5-fluorouracil (5-FU) mono- and combination therapies in JIMT-1 cells, a HER2+ BC cell line exhibiting intrinsic resistance to trastuzumab. Concentration–response relationships and temporal p...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 3, 2021 Category: Drugs & Pharmacology Source Type: research

Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates
In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 3, 2021 Category: Drugs & Pharmacology Source Type: research

PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT
AbstractClazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20  mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consider...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 2, 2021 Category: Drugs & Pharmacology Source Type: research

A pharmacodynamic model of tidal volume and inspiratory sevoflurane concentration in children during spontaneous breathing
AbstractPurposeHigh concentrations of sevoflurane causes respiratory depression, mainly due to the decrease in tidal volume (TV) during spontaneous ventilation. The purpose of this study was to identify clinical variables that affect the relationship between TV and sevoflurane concentration, and to establish a population pharmacodynamic modelling approach to TV and sevoflurane concentration in children. A prospective observational study involving 48 patients ( ≤ 6 years of age) scheduled to undergo general anesthesia using laryngeal mask airway was performed. When the inspiratory sevoflurane concentration reached 2 vol%...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 2, 2021 Category: Drugs & Pharmacology Source Type: research

Improved numerical stability for the bounded integer model
This article highlights some numerical challenges when implementing the bounded integer model for composite score modeling and suggests an improved implementation. The improvement is based on an approximation of the logarithm of the error function. After presenting the derivation of the improved implementation, the article compares the performance of the algorithm to a naive implementation of the log-likelihood using both simulations and a real data example. In the simulation setting, the improved algorithm yielded more precise and less biased parameter estimates when the within-subject variability was small and estimation...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 26, 2020 Category: Drugs & Pharmacology Source Type: research

Detection and impact of hysteresis when evaluating a drug ’s QTc effect using concentration-QTc analysis
AbstractEarly-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quanti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 28, 2020 Category: Drugs & Pharmacology Source Type: research

A novel approach for personalized response model: deep learning with individual dropout feature ranking
AbstractDeep learning is the fastest growing field in artificial intelligence and has led to many transformative innovations in various domains. However, lack of interpretability sometimes hinders its application in hypothesis-driven domains such as biology and healthcare. In this paper, we propose a novel deep learning model with individual feature ranking. Several simulated datasets with the scenarios that contributing features are correlated and buried among non-contributing features were used to characterize the novel analysis approach. A publicly available clinical dataset was also applied. The performance of the indi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 26, 2020 Category: Drugs & Pharmacology Source Type: research

A kinetic proofreading model for bispecific protein degraders
AbstractBispecific protein degraders (BPDs) engage the ubiquitin –proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs that includes the reaction network governing ternary complex formation and degradation via the UPS. A critical element of the model framework is a multi-step process that results in a time delay between ternary complex formation and protein degradation, thereby balancing ternary complex stability against UPS degr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 22, 2020 Category: Drugs & Pharmacology Source Type: research

An integrative model of Parkinson ’s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression
AbstractLevodopa is considered the gold standard treatment of Parkinson ’s disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa’s effect duration and to the appearance of motor complications. This evolution challenges the establishment o f optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson’s disease to evaluate motor function in response to levo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Exact solutions and equi-dosing regimen regions for multi-dose pharmacokinetics models with transit compartments
AbstractCompartmental models which yield linear ordinary differential equations (ODEs) provide common tools for pharmacokinetics (PK) analysis, with exact solutions for drug levels or concentrations readily obtainable for low-dimensional compartment models. Exact solutions enable valuable insights and further analysis of these systems. Transit compartment models are a popular semi-mechanistic approach for generalising simple PK models to allow for delayed kinetics, but computing exact solutions for multi-dosing inputs to transit compartment systems leading to different final compartments is nontrivial. Here, we find exact ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 10, 2020 Category: Drugs & Pharmacology Source Type: research

The application of extreme value theory to pharmacometrics
AbstractClinical trials are often analyzed by examining the means, e.g., what is the mean treatment effect or what is the mean treatment difference, but there are times when analysis of the maximums (or minimums) are of interest. For instance, what is the highest heart rate that could be observed or what the smallest  treatment effect that could be expected? While inference on the means is based on the central limit theorem, the corresponding theorem for maximums or minimums is the Fisher–Tippett theorem, also called the extreme value theorem (EVT). This manuscript will introduce EVT to pharmacometricians, pa rt...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 9, 2020 Category: Drugs & Pharmacology Source Type: research

A general model for cell death and biomarker release from injured tissues
In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 28, 2020 Category: Drugs & Pharmacology Source Type: research

A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients
AbstractPirfenidone and nintedanib are the first two FDA-approved therapies for treatment of idiopathic pulmonary fibrosis (IPF). The clinical programs for pirfenidone and nintedanib included 1132 patients in the placebo arms and 1691 patients in the treatment arms across 6 trials. We developed a disease progression model to characterize the observed variability in lung function decline, measured as percent predicted forced vital capacity (%p-FVC), and its decrease in decline after treatment. The non-linear longitudinal change in %p-FVC was best described by a Weibull function. The median decreased decline in %p-FVC after ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 18, 2020 Category: Drugs & Pharmacology Source Type: research

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 14, 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 13, 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 3, 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 1, 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 30, 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 24, 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 24, 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 17, 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 15, 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 7, 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 7, 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 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