J-P Tillement, Faculty of Medicine of Paris XII, Paris, France D Tremblay, AFSSAPS Consultant (French Agency for Drugs), France
© 2007 Elsevier Ltd. All Rights Reserved.
5.02.1 Introduction 11
5.02.2 Pharmacokinetic Requirements for Drug Development 12
5.02.3 The Fate of Drugs in the Body: The Absorption, Distribution, Metabolism, and Excretion (ADME) Paradigm 13
5.02.3.1 An Overview of Kinetics 13
5.02.3.2 Absorption 13
5.02.3.3 Distribution 14
5.02.3.4 Metabolism 15
5.02.3.5 Excretion 16
5.02.3.5.1 Renal excretion 16
5.02.3.5.2 Hepatic elimination 16
5.02.3.5.3 Other routes of excretion 16
5.02.4 Pharmacokinetic Parameters 17
5.02.4.1 Introduction 17
5.02.4.2 Calculation of Individual Parameters 17
5.02.4.3 Clinical Considerations 21
5.02.5 Bioavailability and Bioequivalence 22
5.02.5.1 Bioavailability 22
5.02.5.2 Bioequivalence 23
5.02.6 Which Pharmacokinetic Profiles for Drugs? 23
5.02.6.1 A Limited Distribution in the Body 24
5.02.6.2 Stable and Predictable Elimination Processes 25
5.02.6.3 Linear Pharmacokinetic Parameters 26
5.02.6.4 One Oral Dose Once a Day 26
5.02.7 Which Pharmacokinetics for Populations at Risk? 26
5.02.8 Conclusion 27 References 28
Combinatorial chemistry and in silico approaches have created an avalanche of new chemical entities (NCEs), which will compete to become drug candidates. Most of these NCEs will be rejected following a thorough selection process, which must be carried out as early as possible for obvious reasons of cost and time.1 The criteria of selection of a drug candidate involve many diverse aspects such as required pharmacological activity, an absence of toxicity at least within a large range of doses including the active ones, and pharmacokinetic characteristics that enable it to develop its activity in human disease.2 These criteria should be weighted simultaneously and balanced. Indeed, the selected agent is not obviously the most powerful one, but the one that satisfies efficacy, safety, and appropriate kinetics. A highly powerful agent that is eliminated from the body too quickly would not be of therapeutic interest. Similarly, a molecule that exhibits a very long half-life (t1/2) may be difficult to monitor and may lead to accumulation in the body. As a result, the selected drug candidate is often a compromise between the needed activity and the toxicological and pharmacokinetic characteristics. The latter allow the fulfillment of this activity and they facilitate prescription, safe use, comedication, and monitoring.
This chapter describes the pharmacokinetic criteria a drug must meet, the principles of their evaluation, and the information needed for rational and safe use in humans, and highlights some new trends in pharmacokinetics.
5.02.2 Pharmacokinetic Requirements for Drug Development
The pharmacological characteristics of a drug involve its pharmacodynamic (PD) and pharmacokinetic (PK) properties. The former include its effects, their mechanisms, and intensity, while the latter include the conditions of the drug's effectiveness, namely its ability to reach and bind to its receptors at pharmacological concentrations over a period of time sufficient for its effects to develop.
Pharmacokinetic studies observe and measure the variations of drug levels in the body as a function of time. They enable the corresponding parameters to be calculated in order to draw models of the fate of the drug allowing for prediction under various conditions. Pharmacokinetics involves studying the concentrations in various parts of the body, namely organs, tissues, blood, and excreta (urine, bile, feces, sweat, saliva, etc.). It involves not only the parent drug (the administered agent) but also its metabolites, be they active, partly active, or inactive. Drug disposition consists of four phases (Figure 1):
• metabolism (i.e., chemical elimination); and
These four phases are not successive but can occur more or less simultaneously in vivo. However, they can be investigated separately in in vitro assays.
Appropriate pharmacokinetic characteristics are needed to fulfill the following therapeutic objectives:
1. To reach the selected targets in amounts high enough to produce pharmacological effects. This objective supposes a body distribution selective enough to avoid high concentrations in tissues or organs where the drug does not act (no receptors) or may lead to toxic effects.
2. To maintain the drug concentrations at sufficient levels over a period of time for the effect to develop.
3. To excrete the parent drug and its metabolites according to stable and predictable processes, avoiding as much as possible interindividual variations due to genetic factors and/or pathophysiological conditions such as diseases that alter drug distribution or excretion. Both in vitro and in vivo assays are needed during drug research and development in order to select a pharmacologically effective agent that will exhibit the best profile for human use.
A number of properties must be assessed during preclinical studies, for example, stability at physiological pH, ability to cross cell membranes by passive diffusion or active transfer, blood distribution, and metabolic stability and profiles. These studies also allow selection of the compulsory second animal species for toxicological testing (the first one often being the rat), since its metabolic profile needs to be close to the human one. This can be done in vitro before long-term toxicological studies begin and the first administration to humans. Metabolic profiles are checked using
Organs (receptors and acceptors)
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