Since modern drug development, drug concentration assays have almost exclusively used plasma as a matrix rather than whole blood. Various theories about assay sensitivity, matrix interference, protein binding, and free drug movement have been put forth to explain why it is “best” to measure drug concentrations in plasma. Personally none of these theories convinces me … Continued
Dose proportionality is a common phrase used pharmacokinetics. Early in the pre-clinical development process, we evaluate dose proportionality in animal species. Then if the drug advances to clinical trials, one of the first assessments in humans is to evaluate dose proportionality. Why is it so important? What do we learn from understanding dose proportionality? What … Continued
PK is the abbreviation for pharmacokinetics. TK is the abbreviation for toxicokinetics. Some consider these to be distinct specialties while others consider them to be the same. Let me explain and then I would like to see what you think. Pharmacokinetics generally deals with doses that are in a therapeutic range. Thus common dose ranges … Continued
The statistical analysis of pharmacokinetic parameters is often overlooked and not always well understood. The disconnect between the pharmacokineticist and the biostatistician can often be a huge stumbling block that prevents the appropriate analysis of PK parameters. While I cannot solve all the disagreements between pharmacokineticists and biostatisticians in a single blog post, I hope … Continued
When constructing pharmacodynamic (PD) models, you will often encounter the adjectives “direct” and “indirect” describing the associated PD model. This terminology was very confusing to me when I was learning about PD modeling. Hopefully a brief explanation will help you. Let’s start with the direct PD model. In this type of model, the drug is … Continued
I am currently attending a short conference on modeling and simulation in pediatric clinical pharmacology, and I noticed that many people in the conference don’t have a good grasp on what “Modeling and Simulation” means. I think most of them think that it is an extremely complicated mathematical concoction that is intended to keep everyone … Continued
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 … Continued
The anticonvulsant properties of phenytoin (PHT) were discovered in 1938. Since then, it has been one of the most widely used antiepileptic drugs. It is slowly absorbed, extensively plasma protein-bound, exhibits a nonlinear, concentration-dependent pharmacokinetic profile, and has a narrow therapeutic range. We determined PHT bioavailability during steady-state therapy by 1) measurement of the two … Continued
Current assessment of drug-drug interaction (DDI) prediction success is based on whether predictions fall within a two-fold range of the observed data. This strategy results in a potential bias toward successful prediction at lower interaction levels [ratio of the area under the concentration-time profile (AUC) in the presence of inhibitor/inducer compared with control is <2]. This scenario can bias any assessment of different DDI prediction algorithms if databases contain large … Continued
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 … Continued
