PHARMACOKINETICS : BASIC CONCEPTS AND APPLICATIONS
Roger VERBEECK
Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism and excretion, and the relationship of these processes to the intensity and time course of therapeutic and toxicologic effects of drugs. The physiologic concepts underlying the fundamental pharmacokinetic processes of absorption, distribution and elimination will be described. The interrelationships among pharmacokinetic parameters and physiologic variables in healthy volunteers and in patients will be demonstrated.
DRUG METABOLISM
The aim of the lectures is to present different aspects of drug metabolism in humans and animals. The first consists of a short overview of phase I and phase II reactions in the liver and elsewhere in the organism. Attention will also be given to stereoselective metabolism. In a second part, the methodology used in drug metabolism studies will be explained : in vitro methods (microsomes, hepatocytes, liver perfusion), in vivo methods (urinary data, intrinsic clearance). The third part will discuss the different factors influencing drug metabolism, such as species, genetic polymorphism, age (neonate, elderly), gender, interactions (induction, inhibition) and disease states. This seminar will focus on some practical aspects of genetic polymorphism of some drug metabolism enzymes. Molecular basis of the variable enzyme activities and methods to genotype individuals will be discussed (debrisoquine - sparteine polymorphism, mephenytoin and N-acetylation polymorphism).CLINICAL PHARMACOKINETICS AND LINKAGE BETWEEN PHARMACOKINETIC AND PHARMACODYNAMIC DATA
This part of the course is focused on non-mathematical pharmacokinetics, describing the core processes of drug absorption, distribution, metabolisation and excretion as a dynamic equilibrium between pharmacokinetic input and output. The main sources of their variability are discussed. Attention is paid to their assessment during drug development and their impact on competitive drug profiling. Examples of 'misleading' and 'confounding' pharmacokinetics are discussed. Finally, the course will consider the linkage between pharmacokinetic and pharmacodynamic data.BIOEQUIVALENCE TESTING
Based on the CHMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence, the following aspects of bioequivalence studies for immediate and modified release oral drug products will be discussed: study design, subject selection, food-interaction studies, pharmacokinetic analysis and statistical evaluation of the data, biowaivers based on the Biopharmaceuticals Classification System (BCS).BIOSTATISTICS
Part I : This part of the course will discuss the fundamental statistical concepts that are essential for professionals in the biomedical sector. Univariate tests of hypotheses, confidence intervals, regression analysis, and some non-parametric tests will be discussed.
Part II : The second part will cover statistical methods required by more elaborate research investigations. Several typical designs of studies will be discussed, including Bayesian and adaptive designs. Techniques for determining the number of subjects required in a clinical trial will be presented.STUDY DESIGNS
The course defines such basic concepts as : biases, blinding, randomisation, parallel versus cross-ver designs, superiority, equivalence and non-inferiority trials.THE PROTOCOL
The protocol is the key reference document of a clinical trial. The homework " Drafting a protocol for a clinical study " will provide a unique opportunity to integrate many aspects of clinical research and provide a competence in reading and understanding protocols.
ETHICAL AND LEGAL ISSUES IN DRUG DEVELOPMENT
Performance of clinical studies has important ethical implications. The course will start with the fundamental concepts of bioethics and the basic documents (Nuremberg code, Declaration of Helsinki). In a more practical way, the rules for functioning of ethical review committees will be presented. The European regulations of clinical trials and their implementation at the national level will be discussed.CLINICAL TRIALS IN DEVELOPING COUNTRIES-CHALLENGES AND OPPORTUNITIES
Traditionally, the majority of clinical development activities sponsored by multinational pharmaceutical companies have been carried out within the context of developed countries. This situation appears to be progressively changing, with more and more clinical trials being conducted in developing countries. Conduct of clinical trials in developing countries must not only follow the same stringent ethical and procedural standards as countries in the developed world, but also, and equally importantly so, there must be a "fair benefit" to study subjects and communities involved. Informed Consent procedure must be followed. Post trial access to study drug has been a controversial topic. Many angles need to be considered, for instance, to whom should this be extended (trial subjects or entire population), and how long for (until launch or life-long) ?GOOD CLINICAL PRACTICE AND SOPs
The ICH-Good Clinical Practice (ICH4-GCP) guidelines for clinical studies will be reviewed in detail. The consequences of the European Directive on Clinical Trials will be discussed.
VACCINES DEVELOPMENT : FROM PRECLINICAL TO CLINICAL STUDIES
The development of new vaccines represents an important challenge. Vaccines are more difficult to characterize analytically than many pharmaceuticals. In addition, correlates of protection against diseases are not always available, making the prediction of the efficacy of many vaccines difficult. The course will describe the preclinical development of vaccines including the selection of vaccination strategy, antigens, adjuvants and vectors, and the selection of animal models for immunogenicity, protection and toxicology studies. Early phases of clinical development will be explained including immunogenicity and safety studies. The challenge of discovering biomarkers of vaccine efficacy in human subjects will be discussed. Finally, the course will describe how preclinical studies are used during the course of the clinical development of vaccines.SPECIFICITIES OF THE CLINICAL DEVELOPMENT PLAN OF BIOLOGICS
This session will address the following issues :
- The different types of biologics and their potential advantages (humanized monoclonal antibodies…)
- The specific toxicity studies in primates
- The issue of placebo control in a population suffering from a severe disease
- Pharmacokinetic peculiarities and measurement of autoantibodies
- The dose-ranging studies.