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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A modeling and simulation-based assessment of the impact of confounding factors on the readout of a sildenafil survival trial in pulmonary arterial hypertension
AbstractSildenafil (REVATIO®) was approved for the treatment of adult Pulmonary Arterial Hypertension (PAH) in the US and the EU. A pediatric study has been performed and sildenafil was approved in the EU for pediatric PAH. The long-term extension of this study revealed good survival but also an increased mortality with the high dose of sildenafil compared to lower doses. As a consequence, FDA required Pfizer to evaluate REVATIO®’s effect on the risk of death in adults with PAH. Following FDA’s rationale a survival model was developed to characterize the exposure–mortality relationship and assess ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 19, 2019 Category: Drugs & Pharmacology Source Type: research

A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia
AbstractCystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 6, 2019 Category: Drugs & Pharmacology Source Type: research

Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients
AbstractUlcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standa...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2019 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation of the modified Rankin Scale and National Institutes of Health Stroke Scale neurological endpoints in intracerebral hemorrhage
AbstractIntracerebral hemorrhage (ICH) is a form of stroke characterized by uncontrolled bleeding into the parenchyma of the brain. There is no approved therapy for ICH and it is associated with very poor neurological outcomes with around half of subjects dying within 1  month and most subjects showing complete or partial disability. A key challenge is to identify subjects who could benefit from intervention using characteristics such as baseline hemorrhage volume and the increase in hemorrhage volume in the first few hours, which have been correlated with final o utcomes in ICH. Combined longitudinal models were deve...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 28, 2019 Category: Drugs & Pharmacology Source Type: research

A quantitative systems pharmacology model of colonic motility with applications in drug development
AbstractWe developed a mathematical model of colon physiology driven by serotonin signaling in the enteric nervous system. No such models are currently available to assist drug discovery and development for GI motility disorders. Model parameterization was informed by published preclinical and clinical data. Our simulations provide clinically relevant readouts of bowel movement frequency and stool consistency. The model recapitulates healthy and slow transit constipation phenotypes, and the effect of a 5-HT4 receptor agonist in healthy volunteers. Using the calibrated model, we predicted the agonist dose to normalize defec...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 19, 2019 Category: Drugs & Pharmacology Source Type: research

Concentration –response modeling of ECG data from early-phase clinical studies to assess QT prolongation risk of contezolid (MRX-I), an oxazolidinone antibacterial agent
AbstractThe effects of contezolid (MRX-I, an oxazolidinone antibacterial agent) on cardiac repolarization were evaluated retrospectively using a population modeling approach in a Phase I study incorporating single ascending dose, multiple ascending dose, and food effect assessments. Linear mixed effect models were used to assess the relationships between MRX-I plasma concentrations and QT/QTc/ ∆QTc (baseline-adjusted), in which different correction methods for heart rate have been included. The upper bound of the one-sided 95% confidence interval (CI) for predicted ∆∆QTc was 
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 12, 2019 Category: Drugs & Pharmacology Source Type: research

Computational framework for predictive PBPK-PD-Tox simulations of opioids and antidotes
AbstractThe primary goal of this work was to develop a computational tool to enable personalized prediction of pharmacological disposition and associated responses for opioids and antidotes. Here we present a computational framework for physiologically-based pharmacokinetic (PBPK) modeling of an opioid (morphine) and an antidote (naloxone). At present, the model is solely personalized according to an individual ’s mass. These PK models are integrated with a minimal pharmacodynamic model of respiratory depression induction (associated with opioid administration) and reversal (associated with antidote administration). ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 7, 2019 Category: Drugs & Pharmacology Source Type: research

Orphan drug development: the increasing role of clinical pharmacology
AbstractOver the last few decades there has been a paradigm shift in orphan drug research and development. The development of the regulatory framework, establishment of rare disease global networks that support drug developments, and advances in technology, has resulted in tremendous growth in orphan drug development. Nevertheless, several challenges during orphan drug development such as economic constraints; insufficient clinical information; fewer patients and thus inadequate power; etc. still exist. While the standard regulatory requirements for drug approval stays the same, applications of scientific judgment and regu...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 22, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients
The article Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients, written by Pierre Chelle, Cindy H. T. Yeung, Santiago Bonanad, Juan Crist óbal Morales Muñoz, Margareth C. Ozelo, Juan Eduardo Megías Vericat, Alfonso Iorio, Jeffrey Spears, Roser Mir, Andrea Edginton, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 21 May 2019 without open access. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 12, 2019 Category: Drugs & Pharmacology Source Type: research

FDA ’s Office of Orphan Products Development: providing incentives to promote the development of products for rare diseases
AbstractThere are nearly 30 million Americans that suffer from at least one of the more than 7000 rare diseases identified to date. Therapies for treating, preventing, or diagnosing rare diseases have been limited due to various reasons. Incentives are provided to sponsors in an effort to promote the development of therapies for rare diseases and to encourage the availability of therapeutically superior drugs or biologics. This paper will discuss the mission of the Office of Orphan Products Development within the Food and Drug Administration (FDA), the specific programs within the office and the relation to incentives prov...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 4, 2019 Category: Drugs & Pharmacology Source Type: research

Automated proper lumping for simplification of linear physiologically based pharmacokinetic systems
AbstractPhysiologically based pharmacokinetic (PBPK) models are an important type of systems model used commonly in drug development before commencement of first-in-human studies. Due to structural complexity, these models are not easily utilised for future data-driven population pharmacokinetic (PK) analyses that require simpler models. In the current study we aimed to explore and automate methods of simplifying PBPK models using a proper lumping technique. A linear 17-state PBPK model for fentanyl was identified from the literature. Four methods were developed to search the optimal lumped model, including full enumeratio...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 20, 2019 Category: Drugs & Pharmacology Source Type: research

Bayesian approach to investigate a two-state mixed model of COPD exacerbations
AbstractChronic obstructive pulmonary disease (COPD) is a chronic obstructive disease of the airways. An exacerbation of COPD is defined as shortness of breath, cough, and sputum production. New therapies for COPD exacerbations are examined in clinical trials frequently based on the number of exacerbations that implies long-term study due to the high variability in occurrence and duration of the events. In this work, we expanded the two-state model developed by Cook et al. where the patient transits from an asymptomatic (state 1) to a symptomatic state (state 2) and vice versa, through investigating different semi-Markov m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 12, 2019 Category: Drugs & Pharmacology Source Type: research

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy
AbstractDrug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such too...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 23, 2019 Category: Drugs & Pharmacology Source Type: research

A translational platform PBPK model for antibody disposition in the brain
AbstractIn this manuscript, we have presented the development of a novel platform physiologically-based pharmacokinetic (PBPK) model to characterize brain disposition of mAbs in the mouse, rat, monkey and human. The model accounts for known anatomy and physiology of the brain, including the presence of distinct blood –brain barrier and blood–cerebrospinal fluid (CSF) barrier. CSF and interstitial fluid turnover, and FcRn mediated transport of mAbs are accounted for. The model was first used to characterize published and in-house pharmacokinetic (PK) data on the disposition of mAbs in rat brain, including the da...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 20, 2019 Category: Drugs & Pharmacology Source Type: research

Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients
This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 20, 2019 Category: Drugs & Pharmacology Source Type: research

Development and evaluation of a generic population pharmacokinetic model for standard half-life factor VIII for use in dose individualization
AbstractHemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Computer-assembled cross-species/cross-modalities two-pore physiologically based pharmacokinetic model for biologics in mice and rats
AbstractTwo-pore physiologically-based pharmacokinetic (PBPK) models can be expected to describe the tissue distribution and elimination kinetics of soluble proteins, endogenous or dosed, as function of their size. In this work, we amalgamated our previous two-pore PBPK model for an inert domain antibody (dAb) in mice with the cross-species platform PBPK model for monoclonal antibodies described in literature into a unified two-pore platform that describes protein modalities of different sizes and includes neonatal Fc receptor (FcRn) mediated recycling. This unified PBPK model was parametrized for organ-specific lymph flow...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 10, 2019 Category: Drugs & Pharmacology Source Type: research

Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems
AbstractGuiding the dose selection for monoclonal antibody oncology drugs is often done using methods for predicting the receptor occupancy of the drug in the tumor. In this manuscript, previous work on characterizing target inhibition at steady state using the AFIR metric (Stein and Ramakrishna in CPT Pharmacomet Syst Pharmacol 6(4):258 –266, 2017) is extended to include a “target-tissue” compartment and the shedding of membrane-bound targets. A new potency metric average free tissue target to initial target ratio (AFTIR) at steady state is derived, and it depends on only four key quantities: the equilib...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 28, 2019 Category: Drugs & Pharmacology Source Type: research

Two-pore physiologically based pharmacokinetic model with de novo derived parameters for predicting plasma PK of different size protein therapeutics
AbstractTwo-pore PBPK models have been used for characterizing the PK of protein therapeutics since 1990s. However, widespread utilization of these models is hampered by the lack of a priori parameter values, which are typically estimated using the observed data. To overcome this hurdle, here we have presented the development of a two-pore PBPK model using de novo derived parameters. The PBPK model was validated using plasma PK data for different size proteins in mice. Using the “two pore theory” we were able to establish the relationship between protein size and key model parameters, such as: permeability-surf...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 25, 2019 Category: Drugs & Pharmacology Source Type: research

Operating characteristics of stepwise covariate selection in pharmacometric modeling
AbstractStepwise covariate modeling (SCM) is a widely used tool in pharmacometric analyses to identify covariates that explain between-subject variability (BSV) in exposure and exposure –response relationships. However, this approach has several potential weaknesses, including over-estimated covariate effect and incorrect selection of covariates due to collinearity. In this work, we investigated the operating characteristics (i.e., accuracy, precision, and power) of SCM in a cont rolled setting by simulating sixteen scenarios with up to four covariate relationships. The SCM analysis showed a decrease in the power to ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 23, 2019 Category: Drugs & Pharmacology Source Type: research

Pitfalls of using numerical predictive checks for population physiologically-based pharmacokinetic model evaluation
AbstractComparisons between observed data and model simulations represent a critical component for establishing confidence in population physiologically-based pharmacokinetic (Pop-PBPK) models. Numerical predictive checks (NPC) that assess the proportion of observed data that correspond to Pop-PBPK model prediction intervals (PIs) are frequently used to qualify such models. We evaluated the effects of three components on the performance of NPC for qualifying Pop-PBPK model concentration –time predictions: (1) correlations (multiple samples per subject), (2) residual error, and (3) discrepancies in the distribution of...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 22, 2019 Category: Drugs & Pharmacology Source Type: research

Reproducible pharmacokinetics
AbstractReproducibility is a highly desired feature of scientific investigation in general, and it has special connotations for research in pharmacokinetics, a vibrant field with over 500,000 publications to-date. It is important to be able to differentiate between genuine heterogeneity in pharmacokinetic parameters from heterogeneity that is due to errors and biases. This overview discusses efforts and opportunities to diminish the latter type of undesirable heterogeneity. Several reporting and research guidance documents and standards have been proposed for pharmacokinetic studies, but their adoption is still rather limi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 18, 2019 Category: Drugs & Pharmacology Source Type: research

Development of visual predictive checks accounting for multimodal parameter distributions in mixture models
AbstractThe assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an indi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 8, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis
This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0 –0.5, 0.5–2, 2–4 and 4–6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment mo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 7, 2019 Category: Drugs & Pharmacology Source Type: research