OBJECTIVES: To characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle). METHODS: The retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III ...

BACKGROUND: Pharmacokinetic and pharmacodynamic (PK/PD) indices are increasingly being used in the microbiological field to assess the efficacy of a dosing regimen. In contrast to methods using MIC, PK/PD-based methods reflect in vivo conditions and are more predictive of efficacy. Unfortunately, they entail the use of one PK-derived value such ...

Allometric scaling is widely used to predict human pharmacokinetic parameters from preclinical species, and many different approaches have been proposed over the years to improve its predictive performance. Nevertheless, prediction errors are commonly observed in the practical application of simple allometry, for example, in cases where the hepatic metabolic clearance ...

In HIV disease, the mechanisms of drug resistance are only poorly understood. Incomplete suppression of HIV by antiretroviral agents is suspected to be a main reason. The objective of this in silico study is to elucidate the pharmacokinetic origins of incomplete viral suppression, exemplified for zidovudine (AZT) as a representative ...

Recent regulatory guidance has highlighted the importance of using pharmacokinetic-pharmacodynamic (PK-PD) modelling in the selection of starting doses in first-in-human trials of high-risk biologics. However, limited examples exist in literature illustrating this procedure. An interpretation of the recommended dose-selection methodology and the minimum anticipated biological effect level (MABEL) principle, contained ...

OBJECTIVE: This study compared the pharmacokinetic/pharmacodynamic (PK/PD) properties of piperacillin/tazobactam (PTZ) combination treatment with those of piperacillin (PIP) monotherapy against clinical gram-negative pulmonary isolates from US patients treated in intensive care units. METHODS: Computer modeling was used to integrate national in vitro microbiologic data from 2002 with pharmacokinetic data from ...

BACKGROUND: An enzyme multiplied immunoassay technique (EMIT) provides convenient and accurate measurements of mycophenolic acid (MPA) concentrations for determination of immunosuppression during treatment with mycophenolate mofetil (MMF). No abbreviated model for estimating the full 12-hour MPA AUC using an EMIT assay in liver transplant recipients has been described previously. OBJECTIVE: ...

Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the sensitizing compound. Previously, our group reported motexafin gadolinium (MGd) concentrations in mouse tissues measured noninvasively by the optical pharmacokinetic system (OPS) in vivo, nondestructively by OPS in ...

PURPOSE: To compare results of population PK analyses obtained with a full empirical design (FD) and an optimal sparse design (MD) in a Drug-Drug Interaction (DDI) study aiming to evaluate the potential CYP3A4 inhibitory effect of a drug in development, SX, on a reference substrate, midazolam (MDZ). Secondary aim was ...

BACKGROUND: The aim of this study was to determine the factors that influence valproate clearance (CL) in Mexican epileptic pediatric patients using a mixed-effect model and sparse data of serum concentrations of valproic acid (VPA) collected during routine clinical care of patients. METHODS: The number of patients included in the ...

PURPOSE: To determine the optimal sampling time design of a drug-drug interaction (DDI) study for the estimation of apparent clearances (CL/F) of two co-administered drugs (SX, a phase I compound, potentially a CYP3A4 inhibitor, and MDZ, a reference CYP3A4 substrate) without any in vivo data using physiologically based pharmacokinetic (PBPK) ...

When modeling is required to describe pharmacokinetics and pharmacodynamics simultaneously, it is difficult to link time-concentration profiles and drug effects. When patients are under chemotherapy, despite the huge amount of blood monitoring numerations, there is a lack of exposure variables to describe hematotoxicity linked with the circulating drug blood levels. ...

Area under the concentration curve (AUC) of mycophenolic acid (MPA) could help to optimize therapeutic drug monitoring during the early post-renal transplant period. The aim of this study was to develop a limited sampling strategy to estimate an abbreviated MPA AUC within the first month after renal transplantation. In this ...

A database of human dermatopharmacokinetic parameters of 12 transdermal patches is established. The effect of system design, application site, and metabolism on pharmacokinetic data is discussed, and interindividual variability of data and its possible sources evaluated. Using multiple regression analysis, two equations based on drugs physicochemical characteristics are suggested for ...

An accurate and precise high-performance liquid chromatographic method using diode array detection for the determination of lamotrigine in human plasma has been developed and validated for use in pharmacokinetic studies. A validation strategy based on the accuracy profiles was used to select the most appropriate regression model and to determine ...

The present study was performed to find the required volume of physiological saline for flushing that will allow the most efficient use of contrast medium during the early phase of dynamic CT. We calculated contrast medium aortic arrival time (AT), time to peak aortic enhancement (TPAE) and the elapsed time ...

The ability to use in vitro human cytochrome P450 (CYP) time-dependent inhibition (TDI) data for in vivo drug-drug interaction (DDI) predictions should be viewed as a prerequisite to generating the data. Important terms in making such predictions are k(inact) and K(I) but first-line screening assays typically involve characterisation of an ...

The relationships between bispectral index (BIS), cardiovascular variables and minimum alveolar concentration (MAC) multiples of sevoflurane in puppies were determined. Five puppies were anesthetized with sevoflurane on two occasions. First, the individual sevoflurane MAC values were determined for each puppy. Secondly, dogs were anesthetized with sevoflurane at each of 5 ...

To investigate the relationship between the degree of liver dysfunction and the pharmacokinetics of docetaxel, a population pharmacokinetic model was developed in an oncology practice without excluding patients with moderate to severe liver dysfunction. Two hundred patients were treated with docetaxel as a single agent or in combination chemotherapy. The ...

A model-based approach was implemented for the development of the proliferator-activated receptor gamma (PPARgamma) agonist rivoglitazone. Population pharmacokinetic and pharmacodynamic models were developed using data collected from 2 phase I and 2 phase II studies in healthy volunteers and participants with type 2 diabetes mellitus. A 2-compartment model with first-order ...

Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety of pathogens. Our objectives were to (i) determine the impact of the CFUo of Pseudomonas aeruginosa on ceftazidime activity and (ii) to develop and validate a pharmacokinetic/pharmacodynamic ...

BACKGROUND: In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade). METHODS: A disposition compartmental ...

A spline-enhanced ordinary differential equation (ODE) method is proposed for developing a proper parametric kinetic ODE model and is shown to be a useful approach to PK/PD model development. The new method differs substantially from a previously proposed model development approach using a stochastic differential equation (SDE)-based method. In the ...

Evaluation of the pharmacokinetics (PKs) in a proper physiological context is paramount to elucidate the factors that may improve a drug's PK properties. Using modern system analysis-based physiological modelling principles, this work applies a novel kinetic analysis framework to a PK comparison of two erythropoietically active drugs, C.E.R.A. (continuous erythropoietin ...

Models for drugs exhibiting target-mediated drug disposition (TMDD) play an important role in the investigation of biological products (Mager and Jusko 2001). These models are often overparameterized and difficult to converge. A simpler quasi-equilibrium (QE) approximation of the general model has been suggested (Mager and Krzyzanski 2005), but even this ...

AIMS: To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS: Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) ...

OBJECTIVE: To characterize the pharmacokinetics of darbepoetin alpha and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration. METHODS: A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were ...

PURPOSE: Our objectives were (1) to compare the disposition and in vivo release of paclitaxel between a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol) in human subjects, and (2) to develop a mechanistic model for unbound and total paclitaxel pharmacokinetics. METHODS: A total of 35 patients (average ...

PURPOSE: Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). METHODS: A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) ...

The ability to accurately quantify indexes of the individual role of glucose (GE(L)) and insulin (S(I)(L)) in the suppression of endogenous glucose production (EGP) would improve the understanding of liver metabolism. Measuring these indexes during an IVGTT by minimal modeling of tracer labeled and unlabeled glucose data is often unreliable, ...

Pharmacokinetic models play a crucial role in analyzing and assessing the results of in vitro and in vivo studies. In this review, comparative analysis of pharmacokinetic models under homogeneous and heterogeneous conditions is performed, placing special focus on the role of fractal theory. The concept of fractals provides a new ...

The quantitative data obtained by emission tomography are decoded using a number of techniques and methods in sequence to provide physiological information. Conventionally, the data are reconstructed to produce a series of static images. Then, pharmacokinetic modeling techniques are applied, and kinetic parameters that have physiological or functional significance are ...

BACKGROUND: Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination. OBJECTIVES: To review the current state of WB-PBPK model use in the clinical phases of drug development. METHODS: A qualitative ...

OBJECTIVES: The aim of this study was to construct the population pharmacokinetic model in Chinese adult patients and to characterize the factors that affect the parameters of remifentanil pharmacokinetics. METHODS: 15 patients were divided randomly into two groups: Index (modeling) group and validation group. 10 patients including 99 blood samples ...

Pharmacokinetics and pharmacodynamics in the newborn are multifaceted: maturation processes of the systems committed to absorption, distribution, metabolism, and excretion partially overlap, making the newborn an extremely dynamic system, especially if compared with adults. In this short note, some of the relevant variables able to regulate these processes are reviewed ...

Population pharmacokinetics (PK)/pharmacodynamics analysis is considered as an important component of drug development process in these days. Owing to different standardization techniques in different laboratories, the drug concentrations in blood are reported in intervals in which they lie. For obvious reason the outcomes are then recorded as multiple discrete indicators ...

INTRODUCTION: Physiological approaches to pharmacokinetic analysis require data on organ sizes and organ blood flows for a given species. An internally consistent compilation of these data for sheep and pigs is needed. Furthermore, it is desirable to be able to appropriately scale these data for individuals of different sizes to ...

Trough (C0) monitoring is not optimal for therapeutic drug monitoring of tacrolimus. To better estimate systemic exposure of tacrolimus and achieve clinical benefit, an improved therapeutic drug monitoring strategy should be developed. The authors examined which single and combination of time points best estimated the empiric "gold standard" AUC0-12h and ...

Limited sampling strategies for estimation of the area under the concentration time curve (AUC) for mycophenolic acid (MPA) co-administered with sirolimus (SRL) have not been previously evaluated. The authors developed and validated 68 regression models for estimation of MPA AUC for two groups of patients, one with concomitant SRL (n ...

Motivated by the use of semiparametric nonlinear mixed-effects modeling on longitudinal data, we develop a new semiparametric modeling approach to address potential structural model misspecification for population pharmacokinetic/pharmacodynamic (PK/PD) analysis. Specifically, we use a set of ordinary differential equations (ODEs) with form dx/dt = A(t)x + B(t) where B(t) is ...

AIMS: To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters. METHODS: PK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously ...

The path of new compounds from discovery to bedside is long and costly and a large majority of compounds never make it to the market. To improve drug development, better tools are needed to assess efficacy and safety early in the process. One approach that has been suggested by the ...

A physiologically based pharmacokinetic (PBPK) model and program (called PostNatal) was developed which focuses on postnatal growth. Algorithms defining organ/tissue growth curves from birth through adulthood for male and female humans, dogs, rats, and mice are utilized to calculate the appropriate weight and blood flow for the internal organs/tissues. This ...

OBJECTIVES: The aim of this study was to develop an integrated system for in vitro pharmacodynamic modelling of antimicrobials with greater flexibility, easier control and better accuracy than existing in vitro models. METHODS: Custom-made bottle caps, fittings, valve controllers and a modified bench-top shaking incubator were used. A temperature-controlled automated ...

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK ...

Quantitative biologically-based models describing key events in the continuum from arsenic exposure to the development of adverse health effects provide a framework to integrate information obtained across diverse research areas. For example, genetic polymorphisms in arsenic metabolizing enzymes can lead to differences in target tissue dosimetry for key metabolites causative ...

OBJECTIVE: The goal of this study was to validate a previously derived and identified physiological subcutaneous (SC) insulin absorption model for computer simulation in a clinical diabetes decision support role using published pharmacokinetic summary measures. METHODS: Validation was performed using maximal plasma insulin concentration (C(max)) and time to maximal concentration ...

The purpose of this study is to develop statistical methodology to facilitate indirect estimation of the concentration of antiretroviral drugs and viral loads in the prostate gland and the seminal vesicle. The differences in antiretroviral drug concentrations in these organs may lead to suboptimal concentrations in one gland. Suboptimal levels ...

OBJECTIVES: The aim of this study was to develop and validate a population pharmacokinetic model for nevirapine in a population of HIV-infected adults and to evaluate the influence of nevirapine dosing regimen and patient characteristics on nevirapine trough concentration. METHODS: HIV-infected adults receiving oral nevirapine for at least 4 weeks ...

Pharmacokinetics after pulmonary administration of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic-pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of ...