At the drug discovery stage, in vivo metabolic hepatic clearance (CL(hep)) is commonly predicted using in vitro parent compound disappearance data generated in liver microsomes or hepatocytes. Correction for the unbound fraction of a compound in the in vitro system and in plasma/serum is known to be critical for the ...

The pK(a) values of 211 discovery (druglike) compounds were determined experimentally using capillary electrophoresis coupled with ultraviolet spectroscopy and a novel fitting algorithm. These values were compared to those predicted by five different commercially available pK(a) estimation packages: ACDLabs/pK(a), Marvin (ChemAxon), MoKa (Molecular Discovery), Epik (Schrodinger), and Pipeline Pilot (Accelrys). ...

Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular ...

BACKGROUND: Propofol and sevoflurane act on the GABA(A) receptor, modulating the function of this receptor in an additive manner. The pharmacodynamic interaction of both drugs considering their effect on EEG activity analysed by the bispectral index (BIS) was identified as additive, but this has not been studied in a clinical ...

A population pharmacokinetic model of doripenem was constructed using data pooled from phase 1, 2, and 3 studies utilizing nonlinear mixed effects modeling. A 2-compartment model with zero-order input and first-order elimination best described the log-transformed concentration-versus-time profile of doripenem. The model was parameterized in terms of total clearance (CL), ...

Two methods of modelling the Double Peak Phenomenon in pharmacokinetics are described; both are based on compartmental models. The first method assumes that the absorption of the drug from the gut to the systemic plasma varies with the location of the drug in the gut, with negligible absorption through the ...

The objective of this study was to implement a semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of ciprofloxacin against Pseudomonas aeruginosa in vitro. Time-kill curves were generated with an initial inoculum close to 5 x 10(6)CFU/ml of P. aeruginosa PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 microg/ml ...

For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults). In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated exponent can be ...

To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration-time curve over 12 h (AUC(0-12)). The pharmacokinetic model of MMF was described ...

Modafinil is being used as a novel wake-promoting psychostimulant. To develop rational dosing schemes, given that China has 56 ethnicities that may have various response to modafinil, it is essential to characterize the population pharmacokinetics of modafinil in some selected ethnicities. One- and two-compartment models were used to fit the ...

REASON FOR PERFORMING STUDY: For legitimate medications, veterinarians must advise the owners or trainers of horses on appropriate withholding times after a treatment, to avoid the risk of incurring a positive drug test. OBJECTIVE: To explore the safety span to select that a veterinarian may extrapolate a tailored withdrawal time ...

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class ...

BACKGROUND: The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation ...

To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man. Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data ...

Background: GFR estimation is of major importance in everyday clinical practice. Usually it is done using one of the many eGFR equations available. In this study we compared in our population four widespread eGFR equations and our own empirical eGFR, with creatinine clearance calculated through a timed urine collection.Patients and ...

This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when ...

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived ...

BACKGROUND: The identification of dogs defective in ATP-binding cassette transporter B1 (ABCB1, MDR1) activity has prompted questions regarding pharmacokinetics (PK), efficacy and toxicity of ABCB1 substrates in these dogs. HYPOTHESIS/OBJECTIVES: Dogs defective in ABCB1 activity (ABCB1(null)) have doxorubicin (DOX) PK different from that of normal dogs (ABCB1(wt)). Utilization of a ...

To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD). PK and PD profiles of human IFN-beta1a, IFN-beta1b, and IFN-alpha2a in humans, monkeys, rats, and mice from nine studies were extracted ...

Mirfazaelian et al. developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal (GI) tract absorption as a saturable process mediated by phase III efflux transporters which pump deltamethrin out of the intestinal enterocytes into the GI tract lumen, resulting in ...

This model-based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy subjects and patients with Parkinson's disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted ...

We investigated the influence of the temporal resolution of dynamic contrast-enhanced MRI data on pharmacokinetic parameter estimation. Dynamic Gd-DTPA (Gadolinium-diethylene triamine pentaacetic acid) enhanced MRI data of implanted prostate tumors on rat hind limb were acquired at 4.7 T, with a temporal resolution of approximately 5 sec. The data were ...

Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-coupled first-order (bi-exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on a ...

NF-kappaB activation is clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The prominent role of IkappaB kinase-2 (IKK-2) in regulating NF-kappaB signaling in response to proinflammatory stimuli has made IKK-2 a primary anti-inflammation therapeutic target. PHA-408, a potent and selective IKK-2 inhibitor, was identified internally and used ...

The plasma effect-site equilibrium rate constant (k(e0)) of propofol has been reported in various pharmacodynamic studies; however, it is not desirable to apply k(e0) for the link with pharmacokinetic models that were separately investigated. Thus, we titrated k(e0) for the pharmacokinetic model, which is known as the multiple covariates adjusted ...

Substantial variability exists among different patients in response to drugs. The identification of genetic factors that contribute to the interpersonal differentiation has been an important task for pharmacogenetic research and drug discovery. In this article, we have derived a high-dimensional statistical model for unveiling the genetic machinery for drug response ...

A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of gemifloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of gemifloxacin at a rate of 4 mg kg of body weight(-1) min(-1) over 50 min. Blood samples were collected for drug assay, ...

BACKGROUND: In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Sh?ttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability ...

Individual variation in drug response is influenced by both genes and environment. We evaluated the potential of a metabolic phenotype to predict individual variation in the pharmacokinetics (PK) of tacrolimus. Liquid chromatography-mass spectroscopy (LC-MS)-based metabolic profiling was performed on 29 healthy volunteers by measuring the levels of 1,256 metabolite ions ...

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) ...

This study presents PKSolver, a freely available menu-driven add-in program for Microsoft Excel written in Visual Basic for Applications (VBA), for solving basic problems in pharmacokinetic (PK) and pharmacodynamic (PD) data analysis. The program provides a range of modules for PK and PD analysis including noncompartmental analysis (NCA), compartmental analysis ...

The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal ...

HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. Data were derived from a phase I study of 26 patients receiving HuHMFG1 at ...

This article describes how a model-based analysis was used to aid development of a novel formulation technology. Paracetamol (acetaminophen) was used as the motivating example with 4 different formulations (2 developmental and 2 commercial) compared using stochastic (Monte Carlo) pharmacokinetic (PK)-pharmacodynamic (PD) simulations to explore potential differences in pharmacodynamic outcomes. ...

INTRODUCTION: It has become apparent in recent years that there is a need for a substantial improvement in the processes used to clarify the inter-relationships between a compound's pharmacokinetic (PK) characteristics, its target actions and its safety profile. This is particularly challenging because most of the techniques currently used to ...

To improve radioimmunotherapy with anti-CD66 antibody, a physiologically based pharmacokinetic (PBPK) model was developed that was capable of describing the biodistribution and extrapolating between different doses of anti-CD66 antibody. METHODS: The biodistribution of the (111)In-labeled anti-CD66 antibody of 8 patients with acute leukemia was measured. The data were fitted to ...

The aim of this study was to evaluate the use of limited blood sampling and Bayesian analysis to estimate the pharmacokinetics (PK) and tailor the dose of factor VIII (FVIII) in an individual patient. In a Bayesian analysis, PK parameters are estimated from only a few plasma concentration measurements, using ...

The once-daily human glucagon-like peptide-1 (GLP-1) analog, liraglutide, was recently shown to provide improved glycemic control in subjects with type 2 diabetes (T2D) compared with exenatide. The aim of this work is to estimate the population pharmacokinetics of liraglutide and make a comparison to the pharmacokinetic profile of exenatide. Pharmacokinetic ...

Proof of concept (POC) may be defined as the earliest point in the drug development process at which the weight of evidence suggests that it is "reasonably likely" that the key attributes for success are present and the key causes of failure are absent. POC is multidimensional but is focused ...

A population pharmacokinetic (PPK) model for enrofloxacin and its metabolite ciprofloxacin in chicken based on retrospective data was developed. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were determined in blood samples from chicken administered either enrofloxacin via oral and intravenous routes or ciprofloxacin via intravenous injection. The disposition of ...

Physiologically based pharmacokinetic (PBPK) models have proven to be successful in integrating and evaluating the influence of age- or gender-dependent changes with respect to the pharmacokinetics of xenobiotics throughout entire lifetimes. Nevertheless, for an effective application of toxicokinetic modelling to chemical risk assessment, a PBPK model has to be detailed ...

OBJECTIVE: To estimate population pharmacokinetic parameters of repaglinide in 121 healthy Malaysian volunteers. METHODS: Each subject received 4 mg of oral repaglinide. Six blood samples were taken per individual (0, 30, 60, 120, 180 and 240 min) for repaglinide's serum concentration determination by using high-performance liquid chromatography. The parametric Iterative ...

In this review, the current approach to predicting hepatic clearance from in vitro metabolic systems is discussed along with a survey of current industry practice. The definitive method of determining intrinsic clearance remains the measurement of Michaelis-Menten parameters derived from metabolite formation rate data. However, in drug discovery this method ...

Animal-to-man extrapolation and therapeutic dose prediction are illustrated with two molecules designed to treat epilepsy. Synaptic vesicle protein 2A (SV2A) is the primary molecular target for their anticonvulsive effect, but additional mechanisms may also contribute. Brivaracetam (BRV), currently in phase 3 of clinical development, was used as the benchmark compound. ...

von Willebrand disease (VWD) Vicenza is characterized by low plasma von Willebrand factor (VWF) levels, the presence of ultra-large (UL) VWF multimers and less prominent satellite bands on multimer gels, and the heterozygous amino acid substitution R1205H in the VWF gene. The pathogenesis of VWD Vicenza has been elusive. Accelerated ...

Effective therapeutic options for Alzheimer's disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound ...

This study presents a new two compartmental model and its application to the evaluation of diclofenac pharmacokinetics in a small number of healthy adults, during a bioequivalence trial. In the model the integer order derivatives are replaced by derivatives of real order often called fractional order derivatives. Physically that means ...

Therapeutic drug monitoring of daily intravenous (IV) busulfan currently requires hospital admission. Population pharmacokinetic modeling and determination of an optimal pharmacokinetic sampling schedule over 6 hours could allow for personalizing these busulfan doses in the outpatient clinic. A retrospective evaluation of daily IV busulfan pharmacokinetics was conducted in 37 adults. ...

A method for predicting the interindividual variability of human exposure for CYP3A4 substrates using Monte Carlo simulation was developed based on relevant factors. The coefficient of variation (CV) values for CYP3A4 content in human liver microsomes, hepatic blood flow, liver volume and body weight, and the unbound blood fraction were ...

Pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation enable the prediction of the effect of a medication in various situations in clinical practice. The aims of this study were to predict the relationships between the effect of rosuvastatin and various factors such as poor compliance, and morning and evening dosages, as well as ...