Special issue: chronopharmacometrics
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 7, 2021 Category: Drugs & Pharmacology Source Type: research

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women
AbstractPopulation pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in 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) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were desc ribed with a two-compartment mode...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 5, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: QTc interval analysis —an ever-evolving endeavor
A correction to this paper has been published: https://doi.org/10.1007/s10928-021-09756-x (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 22, 2021 Category: Drugs & Pharmacology Source Type: research

Comparing the performance of first-order conditional estimation (FOCE) and different expectation –maximization (EM) methods in NONMEM: real data experience with complex nonlinear parent-metabolite pharmacokinetic model
In this study, we compared the performance of FOCE, FOCE FAST, and two EM methods, namely importance sampling (IMP) and stochastic approximation expectation–maximization (SAEM), utilizing the rich pharma cokinetic data of oxfendazole and its two metabolites obtained from the first-in-human single ascending dose study in healthy adults. All methods yielded similar parameter estimates, but great differences were observed in parameter precision and modeling time. For simpler models (i.e., models of oxf endazole and/or oxfendazole sulfone), FOCE and FOCE FAST were more efficient than EM methods with shorter run time and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 21, 2021 Category: Drugs & Pharmacology Source Type: research

Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody
AbstractThe thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modellin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 12, 2021 Category: Drugs & Pharmacology Source Type: research

QTc interval analysis —an ever-evolving endeavor
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 7, 2021 Category: Drugs & Pharmacology Source Type: research

Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions
AbstractCircadian rhythms are ubiquitous phenomena that recur daily in a self-sustaining, entrainable, and oscillatory manner, and orchestrate a wide range of molecular, physiological, and behavioral processes. Circadian clocks are comprised of a hierarchical network of central and peripheral clocks that generate, sustain, and synchronize the circadian rhythms. The functioning of the peripheral clock is regulated by signals from autonomic innervation (from the central clock), endocrine networks, feeding, and other external cues. The critical role played by circadian rhythms in maintaining both systemic and tissue-level hom...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 1, 2021 Category: Drugs & Pharmacology Source Type: research

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse
AbstractA computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of “functional groupings of genes” defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focu s our analysis on four tissues (adipose, liver, lung, and muscle). A genome-wide pathway-centric analysis enables us to develop a comprehensive picture on how the observed circadi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 25, 2021 Category: Drugs & Pharmacology Source Type: research

Applications of cosinor rhythmometry in pharmacology
AbstractStudy design and data analysis are two important aspects relevant to chronopharmacometrics. Blunders can be avoided by recognizing that most physiological variables are circadian periodic. Both ill health and treatment can affect the amplitude, phase, and/or period of circadian (and other) rhythms, in addition to their mean. The involvement of clock genes in molecular pathways related to important physiological systems underlies the bidirectional relationship often seen between circadian rhythm disruption and disease risk. Circadian rhythm characteristics of marker rhythms interpreted in the light of chronobiologic...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 23, 2021 Category: Drugs & Pharmacology Source Type: research

Optimum multi-drug regime for compartment model of tumour: cell-cycle-specific dynamics in the presence of resistance
The objective is to determine the optimal drug schedule according to the patient ’s physiological condition so that the tumour burden is minimised. A multi-objective optimisation algorithm, non-dominated sorting genetic algorithm-II (NSGA-II) is utilised to solve the problem. The obtained results are thoroughly analysed to illustrate the impact of drug resistance on the treatm ent. The capability of optimised schedules to deal with parametric uncertainty is also analysed. The drug schedules obtained in this work align well with the clinical standards. It is also revealed that the NSGA-II optimised drug schedule with ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 22, 2021 Category: Drugs & Pharmacology Source Type: research

A semi-mechanistic exposure –response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases
AbstractVerinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure –response model for uric acid kinetics to include between-subject variability to verinurad and its co...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 17, 2021 Category: Drugs & Pharmacology Source Type: research

Mathematical modeling of mammalian circadian clocks affecting drug and disease responses
AbstractTo align with daily environmental changes, most physiological processes in mammals exhibit a time-of-day rhythmicity. This circadian control of physiology is intrinsically driven by a cell-autonomous clock gene network present in almost all cells of the body that drives rhythmic expression of genes that regulate numerous molecular and cellular processes. Accordingly, many aspects of pharmacology and toxicology also oscillate in a time-of-day manner giving rise to diverse effects on pharmacokinetics and pharmacodynamics. Genome-wide studies and mathematical modeling are available tools that have significantly improv...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 16, 2021 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic characteristics of cemiplimab in patients with advanced malignancies
AbstractCemiplimab, a human monoclonal antibody targeting programmed cell death-1 (PD-1) receptor, demonstrated antitumor activity in patients with advanced malignancies and a safety profile comparable to other anti –PD-1 therapies. This population pharmacokinetics (PopPK) analysis of cemiplimab included 11,178 pharmacokinetics (PK) observations from 548 patients pooled from a first-in-human study (Study 1423; NCT02383212) in advanced malignancies and a Phase 2 study (Study 1540; NCT02760498) in advanced cuta neous squamous cell carcinoma (CSCC). Most patients (80.3%) received cemiplimab 3 mg/kg every 2 wee...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 16, 2021 Category: Drugs & Pharmacology Source Type: research

How circadian variability of the heart rate and plasma electrolytes concentration influence the cardiac electrophysiology – model-based case study
AbstractThe circadian rhythm of cardiac electrophysiology is dependent on many physiological and biochemical factors. Provided, that models describing the circadian patterns of cardiac activity and/or electrophysiology which have been verified to the acceptable level, modeling and simulation can give answers to many of heart chronotherapy questions. The aim of the study was to assess the performance of the circadian models implemented in Cardiac Safety Simulator v 2.2 (Certara, Sheffield, UK) (CSS), as well as investigate the influence ofcircadian rhythms on the simulation results in terms of cardiac safety. The simulation...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 5, 2021 Category: Drugs & Pharmacology Source Type: research

The power of modelling pulsatile profiles
In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12  h post-dose on simulated dense concentration–time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the decon...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 3, 2021 Category: Drugs & Pharmacology Source Type: research

Reduction of quantitative systems pharmacology models using artificial neural networks
In this study, we explore the use of artificial neural networks for approximating an input–output relationship within highly dimensional systems models. We illustrate this approach using a model of blood coagulation. The model consists of two components linked together thro ugh a highly dimensional discontinuous interface, which creates a difficulty for model reduction techniques. The proposed approach enables the development of an efficient approximation to complex models with the desired level of accuracy. The technique is applicable to a wide variety of models and p rovides substantial speed boost for use of such ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 2, 2021 Category: Drugs & Pharmacology Source Type: research

Tribute to Professor Hartmut Derendorf —1953 to 2020: The gentle giant of quantitative clinical pharmacology
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 2, 2021 Category: Drugs & Pharmacology Source Type: research

Constant infusion case of one compartment pharmacokinetic model with simultaneous first-order and Michaelis –Menten elimination: analytical solution and drug exposure formula
AbstractThe main objective of this article is to propose the closed-form solution of one-compartment pharmacokinetic model with simultaneous first-order and Michaelis –Menten elimination for the case of constant infusion. For the case of bolus administration, we have previously established a closed-form solution of the model through introducing a transcendentX function. In the same vein, we found here a closed-form solution of constant infusion could be realized through introducing another transcendentY function. For the general case of constant infusion of limited duration, the closed-form solution is then fully exp...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 24, 2021 Category: Drugs & Pharmacology Source Type: research

Estimating drug potency in the competitive target mediated drug disposition (TMDD) system when the endogenous ligand is included.
AbstractPredictions for target engagement are often used to guide drug development. In particular, when selecting the recommended phase 2 dose of a drug that is very safe, and where good biomarkers for response may not exist (e.g. in immuno-oncology), a receptor occupancy prediction could even be the main determinant in justifying the approved dose, as was the case for atezolizumab. The underlying assumption in these models is that when the drug binds its target, it disrupts the interaction between the target and its endogenous ligand, thereby disrupting downstream signaling. However, the interaction between the target and...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 8, 2021 Category: Drugs & Pharmacology Source Type: research

New Editorial Advisory Board Members and Thank You to Reviewers
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 8, 2021 Category: Drugs & Pharmacology Source Type: research

A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy
AbstractIntermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in act...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 4, 2021 Category: Drugs & Pharmacology Source Type: research

The rhythm of a preterm neonate ’s life: ultradian oscillations of heart rate, body temperature and sleep cycles
The objectives are to characterize oscillations of physiological functions such as heart rate and body temperature, as well as the sleep cycle from behavioral states in generally stable preterm neonates during the first 5 days of life. Heart rate, body temperature as well as behavioral states were collected during a daily 3-h observation interval in 65 preterm neonates within the first 5 days of life. Participants were born before 32  weeks of gestational age or had a birth weight below 1500 g; neonates with asphyxia, proven sepsis or malformation were excluded. In total 263 observation intervals were available. ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

Concentration –QTc analysis for single arm studies
AbstractConcentration –QTc (C–QTc) modeling is being increasingly used in phase 1 studies. For studies without a placebo arm (single arm studies), the scientific whitepaper by Garnett et al. (https://doi.org/10.1007/s10928-017-9558-5) states that time-matched baseline adjustments may minimize the effect of diurnal variation in QTc intervals, and categorical time effects are not needed in the model. However, how diurnal variations can be accounted for when only pre-dose baselines are available is unclear. This research investigates whether including categorical time effects in the model can adjust diurnal variat...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 29, 2021 Category: Drugs & Pharmacology Source Type: research

Do epoch lengths of hypnotic depth indicators affect estimated of blood-brain equilibration rate constants of propofol?
This study aimed to investigate the effect of epoch length of hypnotic depth indicators on the blood –brain equilibration rate constant (ke0) estimates of propofol. Propofol was administered by zero-order infusion (1.5, 3.0, 6, and 12 mg ·kg−1·h−1) for one hour in 63 healthy volunteers. Theke0 of propofol was estimated using an effect-compartment model linking pharmacokinetics and pharmacodynamics, in which response variables were electroencephalographic approximate entropy (ApEn) or bispectral index (BIS) (n = 32 each for propofol infusion rates of 6 and 12 mg ·kg−1·h&mi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 7, 2021 Category: Drugs & Pharmacology Source Type: research

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