Plasma terminal half-life P. L. TOUTAIN & A. BOUSQUET-ME ´ LOU UMR 181 Physiopathologie et Toxicologie Expe´rimentales INRA/ENVT, Ecole Nationale Ve´te´rinaire de Toulouse, Toulouse cedex 03, France Toutain, P. L., Bousquet-Me´lou, A. Plasma terminal half-life. J. vet. Pharmacol. Therap. 27, 427–439. Terminal plasma half-life is the time required to divide the plasma concentra- tion by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. When the process of absorption is not a limiting factor, half-life is a hybrid parameter controlled by plasma clearance and extent of distribution. In contrast, when the process of absorption is a limiting factor, the terminal half-life reflects rate and extent of absorption and not the elimination process (flip-flop pharmacokinetics). The terminal half-life is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations and the time taken to reach equilibrium. P. L. Toutain, UMR 181 Physiopathologie et Toxicologie Expe´rimentales INRA/ ENVT, Ecole Nationale Ve´te´rinaire de Toulouse, 23, chemin des Capelles, 31076 Toulouse cedex 03, France. E-mail: pl.toutain@envt.fr INTRODUCTION The plasma half-life (half-life of elimination or half-life of the terminal phase) is the most frequently reported of all pharmacokinetic parameters. It has the apparent advantage of being a familiar term, immediately comprehensible because it is expressed in units of time. This is not the case for body clearance (the most important pharmacokinetic parameter), which is more difficult to conceive because it has the units of flow. The half-life is (apparently) easy to compute and it is often the only reported pharmacokinetic parameter in some in vitro or in vivo assays. In some circumstances, it is generally the only parameter which can be computed, e.g. for a drug metabolite or any analyte disposition when the dose is unknown. Actually, plasma half-life is very often wholly misunderstood and many non-kineticists continue to mistakenly believe that it represents the time required to eliminate half the administered dose of a drug. In this review, we will re-state the definition of terminal half-life and qualify its pharmacokinetic meaning, which can be very different after intravenous (i.v.) and extra-vascular administra- tion. The clinical relevance of terminal half-life will also be discussed together with its value in the rational selection of dosage interval. Finally, some technical issues concerning its estimation (sampling time and level of quantification of the analytical technique) will be addressed. In this review, the term ‘terminal half-life’ is preferred to ‘elimination half-life’, because it does not prejudge the mechan- ism controlling plasma concentration decay. DEFINITION OF TERMINAL HALF-LIFE Following i.v. administration, the terminal half-life is the time required for plasma/blood concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached; then, terminal half-life is computed when the decrease in drug plasma concentration is due only to drug elimination, and the term ‘elimination half-life’ is applicable. Therefore, it is not the time necessary for the amount of the administered drug to fall by one half. The decay of a drug following first-order pharmacokinetics being exponential, the terminal half-life is obtained from Eqn 1: t 1=2 ¼ 0:693 k z ð1Þ where 0.693 is the natural logarithm of 2 and k z , the slope of the terminal phase. Figure 1 shows two drugs having the same terminal half-life but with very different clearances. In order to express the overall persistence of a drug in the body using a time parameter, then the mean residence time (MRT), and not the terminal plasma half-life, should be selected. The confusion in the definition of half-life is historical. In the early stages of pharmacokinetics, analytical performances were poor and many drug dispositions were described by a single mono-exponential phase. In this situation, and only in this situation, the half-life is also the time it takes to eliminate half the administered dose of the drug. It is also relevant to note that when the pseudo-equilibrium has been reached, the disposition curve becomes mono-exponential and here also, the terminal half-time becomes the time taken to eliminate half the remaining fraction (not half the administered dose). J. vet. Pharmacol. Therap. 27, 427–439, 2004. REVIEW Ó 2004 Blackwell Publishing Ltd 427