Determination of Free 25(OH)D Concentrations and Their Relationships to Total 25(OH)D in Multiple Clinical Populations.

Context: The optimal measure of vitamin D status is unknown.

Objective: To directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.

Design: Cross-sectional analysis.

Determination of Tobramycin in M Medium by LC-MS/MS: Signal Enhancement by Trichloroacetic Acid.

It is well known that ion-pairing reagents cause ion suppression in LC-MS/MS methods. Here, we report that trichloroacetic acid increases the MS signal of tobramycin. To support studies of an pharmacokinetic/pharmacodynamic simulator for bacterial biofilms, an LC-MS/MS method for determination of tobramycin in M media was developed.

Mathematical Modeling of Biofilm Structures Using COMSTAT Data.

Mathematical modeling holds great potential for quantitatively describing biofilm growth in presence or absence of chemical agents used to limit or promote biofilm growth. In this paper, we describe a general mathematical/statistical framework that allows for the characterization of complex data in terms of few parameters and the capability to (i) compare different experiments and exposures to different agents, (ii) test different hypotheses regarding biofilm growth and interaction with different agents, and (iii) simulate arbitrary administrations of agents. The mathematical framework is divided to submodels characterizing biofilm, including new models characterizing live biofilm growth and dead cell accumulation; the interaction with agents inhibiting or stimulating growth; the kinetics of the agents.

Spatiotemporal pharmacodynamics of meropenem- and tobramycin-treated Pseudomonas aeruginosa biofilms.

Objectives: The selection and dose of antibiotic therapy for biofilm-related infections are based on traditional pharmacokinetic studies using planktonic bacteria. The objective of this study was to characterize the time course and spatial activity of human exposure levels of meropenem and tobramycin against Pseudomonas aeruginosa biofilms grown in an in vitro flow-chamber model.

Methods: Pharmacokinetic profiles of meropenem and tobramycin used in human therapy were administered to GFP-labelled P.

New in vitro model to study the effect of human simulated antibiotic concentrations on bacterial biofilms.

A new in vitro pharmacokinetic/pharmacodynamic simulator for bacterial biofilms utilizing flow cell technology and confocal laser scanning microscopy is described. The device has the ability to simulate the changing antibiotic concentrations in humans associated with intravenous dosing on bacterial biofilms grown under continuous culture conditions. The free drug concentrations of a single 2-g meropenem intravenous bolus dose and first-order elimination utilizing a half-life of 0.

Determination of meropenem in bacterial media by LC-MS/MS.

To support the development of a dynamic in vitro human pharmacokinetic/pharmacodynamic simulation model for biofilm-mediated infections and study stability of meropenem, an LC-MS/MS method for the determination of meropenem in Luria Bertani (LB) media was developed and validated in an API2000 LC-MS/MS system. A partial validation was also performed in M9 media. Sample aliquots of 100μL (or 25μL for M9 media) were mixed with the internal standard (IS) ceftazidime and filtered.

Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia.

Objective: To examine the impact of a change in the empiric gentamicin dose from 5 mg kg(-1) every 24 h (Q24 h period) to 5 mg kg every 36 h (Q36 h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.

Study Design: Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24 h period.

Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia.

Study Objective: To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations.

Design: Population pharmacokinetic study using retrospective medical record data.

Setting: Tertiary neonatal intensive care unit.

Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors.

Aim: To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.

Methods: A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used.

Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women.

Objectives: To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa.

Design: In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/μl randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity.

A method to quantify illicit intake of drugs from urine: methamphetamine.

Qualitative urinalysis can verify abstinence of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such as methamphetamine (MA), a single episode of abuse can result in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug use but do not achieve almost complete abstinence are classified as ineffective.

Fractional dynamics pharmacokinetics-pharmacodynamic models.

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics-pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior.

Fractional compartmental models and multi-term Mittag-Leffler response functions.

Systems of fractional differential equations (SFDE) have been increasingly used to represent physical and control system, and have been recently proposed for use in pharmacokinetics (PK) by (J Pharmacokinet Pharmacodyn 36:165-178, 2009) and (J Phamacokinet Pharmacodyn, 2010). We contribute to the development of a theory for the use of SFDE in PK by, first, further clarifying the nature of systems of FDE, and in particular point out the distinction and properties of commensurate versus non-commensurate ones. The second purpose is to show that for both types of systems, relatively simple response functions can be derived which satisfy the requirements to represent single-input/single-output PK experiments.

Population analyses of atorvastatin clearance in patients living in the community and in nursing homes.

The effects of demographic and clinical covariates on the apparent clearance (CL/F) of orally administered atorvastatin, with chronic dosing in a patient population that included the elderly, were studied in 143 patients (atorvastatin: 34 +/- 26 mg/day, mean +/- SD; men (n = 64), age 64.6 +/- 12.1 years, and women (n = 79), age 69.

Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets.

In diacetylmorphine prescription programs for heavily dependent addicts, diacetylmorphine is usually administered intravenously, but this may not be possible due to venosclerosis or when heroin abuse had occurred via non-intravenous routes. Since up to 25% of patients administer diacetylmorphine orally, we characterised morphine absorption after single oral doses of immediate and extended release diacetylmorphine in 8 opioid addicts. Plasma concentrations were determined by liquid chromatography-mass spectrometry.

A mechanistic model for the sex-specific response to nalbuphine and naloxone in postoperative pain.

We develop a mechanistic model for post-operative pain and apply it to describe the pharmacodynamic effects of the kappa-opioids nalbuphine and naloxone administered either alone or in combination in patients after surgical removal of one or more madibular third molar teeth. Data were obtained from 6 clinical studies in which a total of 304 patients were intravenously administered single doses of 2.5, 5, 10 or 20 mg of nalbuphine.

Reversible jump Markov chain Monte Carlo for deconvolution.

To solve the problem of estimating an unknown input function to a linear time invariant system we propose an adaptive non-parametric method based on reversible jump Markov chain Monte Carlo (RJMCMC). We use piecewise polynomial functions (splines) to represent the input function. The RJMCMC algorithm allows the exploration of a large space of competing models, in our case the collection of splines corresponding to alternative positions of breakpoints, and it is based on the specification of transition probabilities between the models.

Improving data reliability using a non-compliance detection method versus using pharmacokinetic criteria.

Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues.

A non-linear mixed effect dynamic model incorporating prior exposure and adherence to treatment to describe long-term therapy outcome in HIV-patients.

Long term therapy with antiretroviral agents in HIV-infected patients often result in failure to suppress the virus load. Imperfect adherence to prescribed antiviral drugs is an important factor explaining the resurgence of virus. A better understanding of the factors responsible for the virological failure is important for the development of new treatment strategies.

Population analyses of amlodipine in patients living in the community and patients living in nursing homes.

Objective: Our objective was to determine the effects of age, sex, and morbidity on the apparent oral clearance (CL/F) of amlodipine.

Methods: Population pharmacokinetic analyses were performed on data from 211 patients receiving oral racemic amlodipine (dose of 7.2 +/- 3.

Pharmacokinetic-pharmacodynamic modelling: history and perspectives.

A major goal in clinical pharmacology is the quantitative prediction of drug effects. The field of pharmacokinetic-pharmacodynamic (PK/PD) modelling has made many advances from the basic concept of the dose-response relationship to extended mechanism-based models. The purpose of this article is to review, from a historical perspective, the progression of the modelling of the concentration-response relationship from the first classic models developed in the mid-1960s to some of the more sophisticated current approaches.

Sample size computations for PK/PD population models.

We describe an accurate, yet simple and fast sample size computation method for hypothesis testing in population PK/PD studies. We use a first order approximation to the nonlinear mixed effects model and chi-square distributed Wald statistic to compute the minimum sample size to achieve given degree of power in rejecting a null hypothesis in population PK/PD studies. The method is an extension of Rochon's sample size computation method for repeated measurement experiments.

The use of a sum of inverse Gaussian functions to describe the absorption profile of drugs exhibiting complex absorption.

Purpose: The aim of this study was to evaluate the utility of a parametric deconvolution method using a sum of inverse Gaussian functions (IG) to characterize the absorption and concentrations vs. time profile of drugs exhibiting complex absorption.

Methods: For a linear time-invariant system the response, Y(t), following an arbitrary input function I(t), is the convolution of I(t) with the disposition function, H(t), of the system: [Formula: see text].

A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation.

Aims: Exemestane (Aromasin) is an irreversible aromatase inactivator used for the treatment of postmenopausal women with advanced breast cancer. The objective of this study was to evaluate the effect of formulation comparing a sugar-coated tablet (SCT) with a suspension and food on the pharmacokinetics (PK) and pharmacodynamics (PD) with respect to plasma estrone sulphate (E1S) concentrations of exemestane, using a PK/PD approach.

Methods: This was an open, three-period, randomized, crossover study.

Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects.

Aim: The combination of ephedrine and caffeine has been used in herbal products for weight loss and athletic performance-enhancement, but the pharmacokinetic profiles of these compounds have not been well characterized. This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects.

Methods: The pharmacokinetic model was developed based on the simultaneous modelling using plasma samples gathered from two clinical trials.