Malcolm Rowland

Lidocaine Pharmacokinetics in Advanced Heart Failure, Liver Disease, and Renal Failure in Humans

Abstract The pharmacokinetics of intravenously administered lidocaine were studied in 10 normal subjects, 11 patients with heart failure, 8 patients with alcoholic liver disease, and 6 chronic rena...

Physiologically-based pharmacokinetics in drug development and regulatory science.

The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine.

Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine

The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first‐pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages at least 65% ± 12% in healthy volunteers and 77% ± 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem, with an average of 86% of the drug absorbed intact from its commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.

A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations.

A dispersion model of hepatic elimination, based on the residence time distribution of blood elements within the liver, is presented. The general rate equations appropriate for describing the hepatic output concentration of a tracer solute are derived. Particular consideration is given to events following a bolus input dose of a tracer. The model is shown to be compatible with the known hepatic architecture and hepatic physiology. The model has been fitted to hepatic outflow data for red blood cells, albumin, and other noneliminated solutes. The experimental data suggest a high degree of dispersion of blood elements within the liver. The model has also been used to evaluate the effects of changes in enzyme activity, hepatic cell permeability, blood flow, and protein binding on the outflow concentration vs. time profiles of solutes.

Mechanistic approaches to volume of distribution predictions: Understanding the processes

PurposeTo use recently developed mechanistic equations to predict tissue-to-plasma water partition coefficients (Kpus), apply these predictions to whole body unbound volume of distribution at steady state (Vuss) determinations, and explain the differences in the extent of drug distribution both within and across the various compound classes.Materials and MethodsVuss values were predicted for 92 structurally diverse compounds in rats and 140 in humans by two approaches. The first approach incorporated Kpu values predicted for 13 tissues whereas the second was restricted to muscle.ResultsThe prediction accuracy was good for both approaches in rats and humans, with 64–78% and 82–92% of the predicted Vuss values agreeing with in vivo data to within factors of ±2 and 3, respectively.ConclusionsGeneric distribution processes were identified as lipid partitioning and dissolution where the former is higher for lipophilic unionised drugs. In addition, electrostatic interactions with acidic phospholipids can predominate for ionised bases when affinities (reflected by binding to constituents within blood) are high. For acidic drugs albumin binding dominates when plasma protein binding is high. This ability to explain drug distribution and link it to physicochemical properties can help guide the compound selection process.

Lidocaine disposition kinetics in monkey and man; I. Prediction by a perfusion model

Lidocaine pharmacokinetics are described in the unanesthetized restrained rhesus monkey after bolus and steady infusion. Simultaneous measurements of systemic and regional blood flows and tissue masses were made in the same animals. Physiologic data are combined in a perfusion model that is predictive of kinetics of lidocaine in the mankey. The model uses eight tissue compartments. Concentrations of lidocaine are described in various tissues at various times. In the first seconds after an intravenous bolus, much at the lidocaine is sequestered by the lungs; then by heart and kidneys and other rapidly perfused tissues. Redistribution then occurs into skeletal muscle and adipose tissue, which accounts for the long observed half‐life of lidocaine. Blood flow and tissue composition data from monkeys can be applied to man to predict blood levels of lidocaine after intravenous injection. The perfusion model is therefore potentially useful in describing and predicting blood levels in states of cardiovascular disease in both monkey and man.

Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs

A volunteer trial was performed to compare the pharmacokinetics of 5 drugs—warfarin, ZK253 (Schering), diazepam, midazolam, and erythromycin—when administered at a microdose or pharmacologic dose. Each compound was chosen to represent a situation in which prediction of pharmacokinetics from either animal or in vitro studies (or both) was or is likely to be problematic.

Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit–risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy–effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy–effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.

Physiologic modeling of cyclosporin kinetics in rat and man

A physiologic pharmacokinetic model of cyclosporin has been developed in the rat aimed at predicting the time course of drug concentrations in blood, organs, and tissues. The model assumes that tissue distribution is perfusion-rate limited and that each tissue acts as a well-stirred compartment. The unbound equilibrium distribution ratios as well as the values of the fraction unbound and the distributon isotherm of cyclosporin between erythrocytes and plasma are included in the rate equations describing the time course of the drug concentration in each tissue. Parameter values for the rat were obtained experimentally from a continuous infusion study, in which 2.7 and I3.9mg/kg per day doses of cyclosporin were administered subcutaneously to each of two groups of rats by osmotic pumps for 6 days. Steady-state cyclosporin concentrations in blood, CSF, and 18 different organs and tissues, were determined by a monoclonal antibody RIA. Differences in values of the unbound equilibrium distribution ratios in some tissues and unbound clearance indicated that both the processes of distribution and elimination may have elements of nonlinearity over the range of dosing rales tested. The model was evaluated in the rat with a kinetic experiment in which a 6-mg/kg dose of cyclosporin was infused intravenously over 15 min, with measurements of blood concentrations until 56 hr. Good agreement was obtained for the volume of distribution at steady state (blood), Vxsbetween the perfusion model and that calculated from the kinetic experiment. Also, the model prediction of the blood concentration temporal profile agreed closely with that observed except in the early moments, when distribution out of blood occurred considerably slower than predicted. On scaling the model up to humans, good agreement was found between the predicted plasma concentration-time profile and Vss,and experimental data from the literature. Both rat and human data suggest that partition into adipose tissue plays an important role in the pharmacokinetics of cyclosporin.

Optimizing the science of drug development : Opportunities for better candidate selection and accelerated evaluation in humans

Two international meetings were convened in 1998 to review the current science of drug development and the potential opportunities to optimize the evaluation of new drugs in humans. This report represents a synopsis of these meetings, and focuses on the current state of knowledge pertaining to drug development, future scientific and technical needs, and the relative merits of various strategies intended to accelerate the clinical development of drugs.