A pharmacokinetic framework describing antibiotic adsorption to cardiopulmonary bypass devices.

Cardiopulmonary bypass (CPB) can alter pharmacokinetic (PK) parameters and the drug may adsorb to the CPB device, altering exposure. Cefazolin is a beta-lactam antibiotic used for antimicrobial prophylaxis during cardiac surgery supported by CPB. Adsorption of cefazolin could result in therapeutic failure.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling.

A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization.

The quality of warfarin treatment may be improved if management is guided by the use of models based upon pharmacokinetic-pharmacodynamic theory. A prospective, two-armed, single-blind, randomized controlled trial compared management aided by a web-based dose calculator (NextDose) with standard clinical care. Participants were 240 adults receiving warfarin therapy following cardiac surgery, followed up until the first outpatient appointment at least 3 months after warfarin initiation.

A physiological approach to renal clearance: From premature neonates to adults.

Aims: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance.

Methods: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

Aims: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students.

Methods: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores).

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

Background And Objective: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations.

Methods: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis.

Consistent methods for fat-free mass, creatinine clearance, and glomerular filtration rate to describe renal function from neonates to adults.

Quantifying the effect of kidney disease on glomerular filtration rate (GFR) is important when describing variability in the clearance of drugs eliminated by the kidney. We aimed to develop a continuous model for renal function (RF) from prematurity to adulthood based on consistent models for fat-free mass (FFM), creatinine production rate (CPR), and GFR. A model for fractional FFM in premature neonates to adults was developed using pooled data from 4462 subjects and 2847 FFM observations.

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients.

Aim: To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians.

Methods: Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics.

Wide size dispersion and use of body composition and maturation improves the reliability of allometric exponent estimates.

To evaluate study designs and the influence of dispersion of body size, body composition and maturation of clearance or reliable estimation of allometric exponents. Non-linear mixed effects modeling and parametric bootstrap were employed to assess how the study sample size, number of observations per subject, between subject variability (BSV) and dispersion of size distribution affected estimation bias and uncertainty of allometric exponents. The role of covariate model misspecification was investigated using a large data set ranging from neonates to adults.

TDM is dead. Long live TCI!

Twenty years ago, target concentration intervention (TCI) was distinguished from therapeutic drug monitoring (TDM). It was proposed that TCI would bring more clinical benefit because of the precision of the approach and the ability to link TCI to principles of pharmacokinetics and pharmacodynamics to predict the dose required by an individual (1). We examine the theory and clinical trial evidence supporting the benefits of TCI over TDM and conclude that in the digital age TDM should be abandoned and replaced by TCI.

Treatment response and disease progression.

This tutorial defines the concepts of disease progression in the context of clinical pharmacology. Disease progression describes the natural history of disease, such as pain, or biomarker of drug response, such as blood pressure. The action of a drug, such as inhibiting an enzyme or activating a receptor, leads to a change in disease status over time.

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention.

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved.

Pharmacodynamic principles and target concentration intervention.

This tutorial reviews the principles of dose individualisation with an emphasis on target concentration intervention (TCI). Once a target effect is chosen then pharmacodynamics can predict the target concentration and pharmacokinetics can predict the target dose to achieve the required response. Dose individualisation can be considered at three levels: population, group and individual.

Negligible impact of birth on renal function and drug metabolism.

Background: Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is uncertain. Increased clearance at birth could reduce analgesic effect attributable to a lowering of plasma concentration.

Pharmacodynamic principles and the time course of delayed and cumulative drug effects.

This tutorial reviews the principles of the concentration - effect relationship for the usual case when drug effects are delayed relative to changes in circulating concentrations. The key processes determining delay are distribution from the circulation to the receptor, binding to the receptor to produce a stimulus and translation of the receptor stimulus into an effect through turnover of physiological mediators. Some clinical outcomes are dependent on the accumulation of drug action which is predictable in terms of basic pharmacokinetic and pharmacodynamic concepts.

Pharmacodynamic principles and the time course of immediate drug effects.

This tutorial defines the principles of the concentration - effect relationship which are the basis of pharmacodynamics. The two key parameters of pharmacodynamics are the maximum response (Emax) and the concentration producing 50% of Emax (C). The time course of effect is illustrated under the assumption that drug effects are immediately related to concentration in the central compartment e.

What is the best size predictor for dose in the obese child?

Lean body mass is commonly proposed for anesthesia maintenance drug dosing calculations. However, total body mass used with allometric scaling has been shown to be better for propofol in obese adults and children. Fat-free mass has also been used instead of lean body mass.

Pharmacokinetic variability due to environmental differences.

This tutorial describes sources of pharmacokinetic variability that are not obviously linked to genetic differences. The sources of variability are therefore described as environmental. The major quantitative sources of environmental variability are body size (including body composition), maturation and organ function.

Why standards are useful for predicting doses.

Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other advantages of this approach including learning about biology, comparing different studies, detecting errors and rationalizing dose prediction. A standard approach to size and maturation is not a panacea but provides the framework for challenging new ideas and supports a consistent method of dosing in patients of all ages.