Pharmacodynamic models of age-structured cell populations
Abstract The purpose of this work is to review basic pharmacodynamic (PD) models describing drug effects on cell populations and expand them to age-structured models using the theory of physiologically structured populations. The plasma drug concentrations are interpreted as the environment affecting the cell production and mortality rates. An explicit solution to model equations provides the age density distribution that serves to establish a relationship between the cell lifespan distribution and the hazard of cell removal. Given the lifespan distributions, the age distributions for most commonly applied PD mode...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 16, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics
Abstract Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biologi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

Abstracts Accepted for American Conference on Pharmacometrics 2015 (ACoP6)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

The American Conference on Pharmacometrics 2015 (ACoP6)
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

Program
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys
Abstract Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 12, 2015 Category: Drugs & Pharmacology Source Type: research

Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l -lactate in rats
In conclusion, we developed a semi-mechanistic kidney model that can be used to evaluate transporter-mediated active renal reabsorption of drugs by the kidney. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice
Abstract A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization. The cytotoxic effects of treatment were described by the kinetics ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

Prediction and validation of enzyme and transporter off-targets for metformin
In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved in the intestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - September 3, 2015 Category: Drugs & Pharmacology Source Type: research

Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models
The objective of his research was to study inter-individual variation in pharmacodynamics. To this end, theoretical concepts and experimental approaches were introduced, which enabled assessment of the changes in pharmacodynamics per se, while excluding or accounting for the cofounding effects of concomitant changes in pharmacokinetics. These concepts were applied in several studies. The results, which were published in 45 papers in the years 1984–1994, showed considerable variation in pharmacodynamics. These initial studies on kinetics of drug action in disease states triggered further experimental research on the r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 30, 2015 Category: Drugs & Pharmacology Source Type: research

Bayesian population modeling of drug dosing adherence
Abstract Adherence is a frequent contributing factor to variations in drug concentrations and efficacy. The purpose of this work was to develop an integrated population model to describe variation in adherence, dose-timing deviations, overdosing and persistence to dosing regimens. The hybrid Markov chain–von Mises method for modeling adherence in individual subjects was extended to the population setting using a Bayesian approach. Four integrated population models for overall adherence, the two-state Markov chain transition parameters, dose-timing deviations, overdosing and persistence were formulated and cr...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 29, 2015 Category: Drugs & Pharmacology Source Type: research

Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
Abstract Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 28, 2015 Category: Drugs & Pharmacology Source Type: research

Modeling population heterogeneity in viral dynamics for chronic hepatitis C infection: Insights from Phase 3 telaprevir clinical studies
Abstract Viral dynamic modelling has proven useful for designing clinical studies and predicting treatment outcomes for patients infected with the hepatitis C virus. Generally these models aim to capture and predict the on-treatment viral load dynamics from a small study of individual patients. Here, we explored extending these models (1) to clinical studies with numerous patients and (2) by incorporating additional data types, including sequence data and prior response to interferon. Data from Phase 3 clinical studies of the direct-acting antiviral telaprevir (T; total daily dose of 2250 mg) combined with pe...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 19, 2015 Category: Drugs & Pharmacology Source Type: research

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities
Abstract Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is develop...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 11, 2015 Category: Drugs & Pharmacology Source Type: research

Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells
Abstract Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 8, 2015 Category: Drugs & Pharmacology Source Type: research

Application of a Bayesian approach to physiological modelling of mavoglurant population pharmacokinetics
Abstract Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug–drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanisti...
Source: Journal of Pharmacokinetics and Pharmacodynamics - August 1, 2015 Category: Drugs & Pharmacology Source Type: research

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times
Abstract Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse samplin...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 26, 2015 Category: Drugs & Pharmacology Source Type: research

Biomarker- versus drug-driven tumor growth inhibition models: an equivalence analysis
Abstract The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic–pharmacodynamic (PK–PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor gro...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 26, 2015 Category: Drugs & Pharmacology Source Type: research

Identifiability of PBPK models with applications to dimethylarsinic acid exposure
Abstract Any statistical model should be identifiable in order for estimates and tests using it to be meaningful. We consider statistical analysis of physiologically-based pharmacokinetic (PBPK) models in which parameters cannot be estimated precisely from available data, and discuss different types of identifiability that occur in PBPK models and give reasons why they occur. We particularly focus on how the mathematical structure of a PBPK model and lack of appropriate data can lead to statistical models in which it is impossible to estimate at least some parameters precisely. Methods are reviewed which can deter...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 21, 2015 Category: Drugs & Pharmacology Source Type: research

A PBPK model describing a xenobiotic with a short PK event scale
Abstract Physiologically-based pharmacokinetic (PBPK) modeling has been widely used in human risk assessment and in early drug development to predict human PK from in vitro and/or in vivo animal data. Recently, the application of PBPK modeling has been extended to the evaluation of drug–drug interactions. For most xenobiotic agents, the PK event scale such as elimination is in hours or days. This is much longer than the transit time of the agent in the body, and a PBPK model can be significantly simplified through lumping based on the physiochemical properties, mass transfer, and biotransformation. However, ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 9, 2015 Category: Drugs & Pharmacology Source Type: research

The method of averaging applied to pharmacokinetic/pharmacodynamic indirect response models
Abstract The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profil...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 4, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and pharmacodynamics of 3,3′-diindolylmethane (DIM) in regulating gene expression of phase II drug metabolizing enzymes
In this study, we sought to characterize the pharmacokinetics of DIM and to build a pharmacokinetic (PK) and pharmacodynamic (PD) model of the DIM-induced gene expression of phase II drug metabolizing enzymes (DME), which potentially links DIM’s molecular effects to its in vivo chemopreventive efficacy. DIM (10 mg/kg) was administered intravenously (i.v.) to male Sprague–Dawley rats and blood samples were collected at selected time points for 48 h. The plasma concentration of DIM was determined using a validated HPLC method. The mRNA expression of NQO1, GSTP1 and UGT1A1 in blood lymphocytes was measur...
Source: Journal of Pharmacokinetics and Pharmacodynamics - July 3, 2015 Category: Drugs & Pharmacology Source Type: research

A semi-mechanistic model of bone mineral density and bone turnover based on a circular model of bone remodeling
Abstract Development of novel therapies for bone diseases can benefit from mathematical models that predict drug effect on bone remodeling biomarkers. Therefore, a bone cycle model (BCM) was developed that takes into consideration the concept of the basic multicellular unit and the dynamic equilibrium of bone remodeling. The model is a closed form cyclical model with four compartments representing resorption, formation, primary mineralization, and secondary mineralization. Equations describing the time course of bone turnover biomarkers were developed using the flow rate of bone cycle units (BCU) between the compa...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 30, 2015 Category: Drugs & Pharmacology Source Type: research

Using early biomarker data to predict long-term bone mineral density: application of semi-mechanistic bone cycle model on denosumab data
Abstract Osteoporosis is a chronic skeletal disease characterized by low bone strength resulting in increased fracture risk. New treatments for osteoporosis are still an unmet medical need because current available treatments have various limitations. Bone mineral density (BMD) is an important endpoint for evaluating new osteoporosis treatments; however, the BMD response is often slower and less profound than that of bone turnover markers (BTMs). If the relationship between BTMs and BMD can be quantified, the BMD response can be predicted by the changes in BTM after a single dose; therefore, a decision based on BM...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 30, 2015 Category: Drugs & Pharmacology Source Type: research

Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids
Abstract The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time. The model adequateness was evaluated by various approaches including visual predictive check (VPC), prediction-correcte...
Source: Journal of Pharmacokinetics and Pharmacodynamics - June 23, 2015 Category: Drugs & Pharmacology Source Type: research

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model
Abstract One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some of the practical obstacles to determining the PK/PD index that best correlates with efficacy. Here, we present ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 31, 2015 Category: Drugs & Pharmacology Source Type: research

Incorporation of stochastic variability in mechanistic population pharmacokinetic models: handling the physiological constraints using normal transformations
Abstract The utilisation of physiologically-based pharmacokinetic models for the analysis of population data is an approach with progressively increasing impact. However, as we move from empirical to complex mechanistic model structures, incorporation of stochastic variability in model parameters can be challenging due to the physiological constraints that may arise. Here, we investigated the most common types of constraints faced in mechanistic pharmacokinetic modelling and explored techniques for handling them during a population data analysis. An efficient way to impose stochastic variability on the parameters ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 26, 2015 Category: Drugs & Pharmacology Source Type: research

Reporting guidelines for population pharmacokinetic analyses
Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 30, 2015 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects
The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an “episodic” manner, i.e., fo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 21, 2015 Category: Drugs & Pharmacology Source Type: research

The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments
The objective of the current investigation was therefore (a) to demonstrate the feasibility of applying nonlinear mixed effects modelling for the evaluation of toxicokinetics and (b) to assess the bias and accuracy in summary measures of systemic exposure for each method. Here, simulation scenarios were evaluated, which mimic toxicology protocols in rodents. To ensure differences in pharmacokinetic properties are accounted for, hypothetical drugs with varying disposition properties were considered. Data analysis was performed using non-compartmental methods and nonlinear mixed effects modelling. Exposure levels were expres...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 14, 2015 Category: Drugs & Pharmacology Source Type: research

Model-based assessment of erlotinib effect in vitro measured by real-time cell analysis
Abstract Real time cell analysis (RTCA) is an impedance-based technology which tracks various living cell characteristics over time, such as their number, morphology or adhesion to the extra cellular matrix. However, there is no consensus about how RTCA data should be used to quantitatively evaluate pharmacodynamic parameters which describe drug efficacy or toxicity. The purpose of this work was to determine how RTCA data can be analyzed with mathematical modeling to explore and quantify drug effect in vitro. The pharmacokinetic-pharmacodynamic erlotinib concentration profile predicted by the model and its effect ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 31, 2015 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment
Abstract This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40–200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC met...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 29, 2015 Category: Drugs & Pharmacology Source Type: research

Development and application of an aggregate adherence metric derived from population pharmacokinetics to inform clinical trial enrichment
This study describes development of an aggregate adherence measure based on population pharmacokinetics (PK), and its comparison to a subjective questionnaire, the Morisky 8-item medication adherence scale (MMAS8), in a trial of psychiatric patients on stable doses of oral aripiprazole. A comprehensive model was first built using plasma drug concentration data from 24 clinical studies comprising 448 patients with over 13,500 observations. Application of this model to independent patient profiles for a given drug-dosing regimen were used to generate the primary aggregate adherence metric, a ratio of observed versus expected...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 29, 2015 Category: Drugs & Pharmacology Source Type: research

Development of a paediatric population pharmacokinetic model for valacyclovir from literature non-compartmental values originating from sparse studies and Bayesian priors: a simulation study
Abstract A preliminary population pharmacokinetic (PopPK) model of valacyclovir in children was developed from non-compartmental analysis (NCA) parameter values from literature, including several age groups, combined with Bayesian priors from a PopPK model of acyclovir, the active metabolite of valacyclovir, from literature too. Also a simulation study was carried out to evaluate the performance of various modelling choices related to the estimation of model parameters from NCA parameters originating from sparse PK studies. Assuming a one-compartment model with first order absorption, a mixed effects, meta-analysi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 28, 2015 Category: Drugs & Pharmacology Source Type: research

Using sensitivity equations for computing gradients of the FOCE and FOCEI approximations to the population likelihood
Abstract The first order conditional estimation (FOCE) method is still one of the parameter estimation workhorses for nonlinear mixed effects (NLME) modeling used in population pharmacokinetics and pharmacodynamics. However, because this method involves two nested levels of optimizations, with respect to the empirical Bayes estimates and the population parameters, FOCE may be numerically unstable and have long run times, issues which are most apparent for models requiring numerical integration of differential equations. We propose an alternative implementation of the FOCE method, and the related FOCEI, for paramet...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 24, 2015 Category: Drugs & Pharmacology Source Type: research

Improved precision of exposure–response relationships by optimal dose-selection. Examples from studies of receptor occupancy using PET and dose finding for neuropathic pain treatment
Abstract An understanding of the relationship between drug exposure and response is a fundamental basis for any dosing recommendation. We investigate optimal dose-selection for two different types of studies, a receptor occupancy study assessed by positron emission tomography (PET) and a dose-finding study in neuropathic pain treatment. For the PET-study, an inhibitory E-max model describes the relationship between drug exposure and displacement of a radioligand from specific receptors in the brain. The model has a mechanistic basis in the law of mass action and the affinity parameter (Ki PL ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 20, 2015 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic and pharmacodynamic model of propofol externally validated in children
Abstract There have been no pharmacokinetic parameters and blood–brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Status 1–2 children aged 2–12 years were given an intravenous bolus of propofol (3 mg kg−1), followed by infusion (200 µg kg−1 min−1). Arterial drug concentrations and bispectral index (BIS) values were m...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 28, 2015 Category: Drugs & Pharmacology Source Type: research

Closed form solutions and dominant elimination pathways of simultaneous first-order and Michaelis–Menten kinetics
Abstract The current study aims to provide the closed form solutions of one-compartment open models exhibiting simultaneous linear and nonlinear Michaelis–Menten elimination kinetics for single- and multiple-dose intravenous bolus administrations. It can be shown that the elimination half-time ( \(t_{1/2}\) ) has a dose-dependent property and is upper-bounded by \(t_{1/2}\) of the first-order elimination model. We further analytically distinguish the dominant role of different elimination pathways in terms of model pa...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 13, 2015 Category: Drugs & Pharmacology Source Type: research

A PBPK workflow for first-in-human dose selection of a subcutaneously administered pegylated peptide
Abstract Predicting the pharmacokinetic (PK) time course of a subcutaneously (SC) administered novel therapeutic protein using in silico approaches offers an opportunity to streamline the drug development process by facilitating selection of starting and target doses in initial human trials. Herein, we propose a workflow for predicting the human exposure time course following SC administration. Leveraging knowledge obtained following both intravenous and SC administration in monkeys, this workflow employs the development of a whole body physiologically-based pharmacokinetic (PBPK) model incorporating vascular circ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 4, 2015 Category: Drugs & Pharmacology Source Type: research

Usefulness of permutation entropy as an anesthetic depth indicator in children
Abstract Permutation entropy (PE) as a complexity measure has been introduced to monitor anesthetic depth for adult. However, PE has not yet been evaluated for its clinical applicability as an indicator of anesthetic depth in children. Therefore, in order to investigate the validity of PE, we compared PE with BIS using pharmacodynamic (PD) modeling in children. Electroencephalogram (EEG) was obtained from BIS monitor during sevoflurane deepening and lightening protocol. End-tidal sevoflurane concentration (Etsevo) and BIS were measured simultaneously. PE was calculated from the processed EEG with the scale ranging...
Source: Journal of Pharmacokinetics and Pharmacodynamics - February 4, 2015 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and pharmacodynamics of propofol in cancer patients undergoing major lung surgery
Abstract Despite the growing number of cancer cases and cancer surgeries around the world, the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetics used in this population are poorly understood. Patients operated due to cancer are usually in severe state and often require chemotherapy. It might affect the PK/PD of drugs used in this population. Therefore, in this study we explored the PK/PD of propofol in cancer patients having a major lung surgery. 23 patients that underwent a propofol–fentanyl total intravenous anesthesia were included in the analysis. A large set of demographic, b...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 28, 2015 Category: Drugs & Pharmacology Source Type: research

Integrated PK-PD and agent-based modeling in oncology
Abstract Mathematical modeling has become a valuable tool that strives to complement conventional biomedical research modalities in order to predict experimental outcome, generate new medical hypotheses, and optimize clinical therapies. Two specific approaches, pharmacokinetic-pharmacodynamic (PK-PD) modeling, and agent-based modeling (ABM), have been widely applied in cancer research. While they have made important contributions on their own (e.g., PK-PD in examining chemotherapy drug efficacy and resistance, and ABM in describing and predicting tumor growth and metastasis), only a few groups have started to comb...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 15, 2015 Category: Drugs & Pharmacology Source Type: research

Development of a physiologically based pharmacokinetic model for a domain antibody in mice using the two-pore theory
The objective of this work was to develop a physiologically-based pharmacokinetic model to investigate the biodisposition of a non-specific dAb construct in mice. Following a single IV administration of 10 mg/kg dummy dAb protein to twenty four female mice, frequent blood samples were collected and whole body lateral sections were analyzed by quantitative whole-body autoradiography. The model is based on the two-pore hypothesis of extravasation where organ-specific isogravimetric flow rates (Jorg,ISO) and permeability-surface area products (PSorg) are expressed as linear functions of the lymph flow rate (Jorg) and the...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 11, 2015 Category: Drugs & Pharmacology Source Type: research

Simulations of site-specific target-mediated pharmacokinetic models for guiding the development of bispecific antibodies
Abstract Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment fo...
Source: Journal of Pharmacokinetics and Pharmacodynamics - January 5, 2015 Category: Drugs & Pharmacology Source Type: research

Modeling energy intake by adding homeostatic feedback and drug intervention
Abstract Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 12, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic–pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice
The objective of this study was to develop a PK–PD model to accurately simulate hepatic ASO concentration and its efficacy from plasma ASO concentration. After single subcutaneous administration of an ASO targeting hepatic apolipoprotein B (Apo-B) mRNA to mice, the ASO was absorbed rapidly and showed biphasic decline with time from the plasma and liver (t1/2: 1–3 and 81–183 h, Tmax: 0.25–0.50 and 4–8 h). After administration, hepatic Apo-B mRNA and plasma total cholesterol began decreasing at 4–8 and 8–24 h, and their Tmax values were observed at 24–72 and 72&n...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 7, 2014 Category: Drugs & Pharmacology Source Type: research

Modeling and simulation of the exposure–response and dropout pattern of guanfacine extended-release in pediatric patients with ADHD
Abstract Guanfacine extended-release (GXR) is a selective α2A-adrenergic receptor agonist approved in the United States for once-daily administration for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents ages 6–17 years old either as monotherapy or adjunctive to stimulant medications. This analysis integrates exposure–response, placebo, and dropout data from 10 clinical trials that used GXR in adolescents and children with ADHD. In these trials, the ADHD Rating Scale-IV (ADHD RS-IV) score was collected longitudinally within patients over the course ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - November 6, 2014 Category: Drugs & Pharmacology Source Type: research

Simulation studies on the estimation of total area under the curve in the presence of right-tailed censoring
Abstract The effect of extrapolated area (%AUCextrap) on estimating mean AUCinf in a simulated single-dose clinical trial was examined. Concentration–time (C–t) profiles from 12 to 36 subjects for 1- and 2-compartment models after single dose administration were simulated with increasing right-tailed censoring. Each subject’s %AUCextrap and AUCinf was calculated using eight different methods, including noncompartmental analysis (NCA), population-based methods, and maximum likelihood (ML) accounting for censoring. Each method’s geometric mean AUCinf and percent relative error (PRE) from ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 31, 2014 Category: Drugs & Pharmacology Source Type: research

In vitro simulation of in vivo pharmacokinetic model with intravenous administration via flow rate modulation
Abstract The aim of this paper was to propose a method of flow rate modulation for simulation of in vivo pharmacokinetic (PK) model with intravenous injection based on a basic in vitro PK model. According to the rule of same relative change rate of concentration per unit time in vivo and in vitro, the equations for flow rate modulation were derived using equation method. Four examples from literature were given to show the application of flow rate modulation in the simulation of PK model of antimicrobial agents in vitro. Then an experiment was performed to confirm the feasibility of flow rate modulation method usi...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 29, 2014 Category: Drugs & Pharmacology Source Type: research

A review of quantitative modeling of B cell responses to antigenic challenge
Abstract A key role of B cells in the mammalian immune response is the generation of antibodies that serve to protect the organism against antigenic challenges. The same process may also be detrimental in the context of autoimmunity. Several modeling approaches have been applied to this aspect of the immune response, from predicting potential epitopes to describing B cells progress through developmental models and simulating antibody production. Here we review some of the modeling techniques, and summarize models that describe different activation mechanisms for B cells, including T cell dependent and independent ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - October 19, 2014 Category: Drugs & Pharmacology Source Type: research