Pharmacokinetics

Pharmacokinetics (PK) and Pharmacodynamic (PD) Analyses

Our biostatistican uses population pharmacokinetics (PK) and pharmacodynamic (PD) models to describe the time course of individual patient exposure and response to a new treatment.

Medistat Ltd. provides expertise in clinical pharmacology to the pharmaceutical industry. Medistat Ltd. client list includes most of the major pharmaceutical and many smaller companies.

PK is the study of how the body processes a drug and PD is the study of how the drug acts on the body. Population PK/PD models are used to determine how patient factors such as demographics, disease status and progression, and co-medications,might affect patient exposure to drug and their subsequent response.

The models can be used to simulate different dose regimens and treatment options. The simulation results can then help design more informative and powerful clinical studies.

Drug development can be a lengthy and costly process and many new drug candidates fail during clinical trials. Many new drugs present a mixed picture of efficacy and toxicity, making development decisions difficult.

Population PK/PD analysis allows for more efficient use of clinical trial results for decision making in several ways:

1) it can provide better insights as to how patients tolerate and respond to a new drug

2) it can shorten development time via the conduct of informative trials

3) it can help identify drug candidates that are unlikely to meet target clinical therapeutic goals early in development.

The use of these methods allows more rapid identification of appropriate dose regimens so fewer clinical trials are needed. The ability to make timely and well informed development decisions translates to major cost savings.

Pharmacodynamic (PD) analyses evaluate the treatment effect on selected blood parameters levels.

Parametric or non-parametric methods are applied to analyze the changes of blood parameters levels from baseline to each time point following treatment.

Pharmacokinetic – A closer look

Pharmacokinetic parameters (calculated based on the plasma concentrations measures):

• C-max – Maximum concentration achieved
• T-max – Time to reach maximum concentration
• AUC0-t – The area under the concentration vs. Time curve, calculated as sum of AUCs using linear trapezoidal summation from time 0 to the last measurable data point
• λz (Lambda-z) – Individual estimate of the terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.
• AUC0-inf – The area under the plasma concentration-time curve extrapolated to infinity, calculated as: AUC0-inf =AUC0-t + Clast / λz, where Clast is the last measurable concentration.

Pharmacokinetics (PK) and Pharmacodynamic (PD) Analyses

• T1/2 – Apparent terminal elimination half-life time, defined as 0.693 / λz.

Pharmacokinetic parameters derived from measures of concentration (AUCs and Cmax) are analyzed using Analysis of Variance (ANOVA). ANOVA model includes treatment, sequence, period, and subject within sequence as the classification variables.

The data is transformed prior to analysis using a logarithmic transformation.

90% Confidence Interval (CI) is constructed for the least squares geometric mean ratios (GMR) for testing formulations Treatment/Reference, using the two one-sided t-tests procedure.