Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions.

Physiologically based pharmacokinetic modeling 1: Predicting the tissue distribution of moderate‐to‐strong bases

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.

Physiologically-based pharmacokinetics in drug development and regulatory science.

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

Coexistence of passive and carrier-mediated processes in drug transport

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

To 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. Vuss 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. The 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. Generic 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.

Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes

Tissue Distribution of Basic Drugs: Accounting for Enantiomeric, Compound and Regional Differences Amongst β-Blocking Drugs in Rat

We address the problem of designing pharmacokinetic experiments in multivariate response situations. Criteria, based on the Fisher information matrix, whose inverse according to the Rao–Cramer inequality is the lower bound of the variance–covariance matrix of any unbiased estimator of the parameters, have previously been developed for univariate response for an individual and a population. We extend these criteria to design individual and population studies where more than one response is measured, for example, when both parent drug and metabolites are measured in plasma, multi-compartment models, where measurements are taken at more than one site, or when drug concentration and pharmacodynamic data are collected simultaneously. We assume that measurements made at distinct times are independent, but measurements made of each concentration are correlated with a response variance–covariance matrix. We investigated a number of optimisation algorithms, namely simplex, exchange, adaptive random search, simulated annealing and a hybrid, to maximise the determinant of the Fisher information matrix as required by the D-optimality criterion. The multiresponse optimal design methodology developed was applied in two case studies, where the aim was to suggest optimal sampling times. The first was a restrospective iv infusion experiment aimed to characterise the disposition kinetics of tolcapone and its two metabolites in healthy volunteers. The second was a prospective iv bolus experiment designed to estimate the tissue disposition kinetics of eight beta-blockers in rat.

Trudy Rodgers

Papers

Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions.

Physiologically based pharmacokinetic modeling 1: Predicting the tissue distribution of moderate‐to‐strong bases

Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes

Tissue Distribution of Basic Drugs: Accounting for Enantiomeric, Compound and Regional Differences Amongst β-Blocking Drugs in Rat

Optimal design for multivariate response pharmacokinetic models.