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By John D. Davis

John Davis-finalNo doubt all pharmaceutical scientists are familiar with the concept of half-life. In fact, many will use the term on an almost daily basis. For Clinical Pharmacology and Translational Research (CPTR) section members, it is a parameter that is used in discussions of appropriate doses and dosing intervals with many different scientists and clinicians, but it can also be the source of confusion and misinterpretation.

Half-life is defined as the time required for half the quantity of a drug or other substance deposited in a living organism to be metabolized or eliminated by normal biological processes. In pharmacokinetics (PK), the behavior of many drugs can often be described using the exponential form, where the amount (but more usually the concentration) of drug being measured falls in a concentration-independent fashion. A drug product’s information sheet typically includes its terminal half-life in blood/plasma/serum, referring to the decline of concentration over time following its administration. This number might be helpful to a prescriber or a patient, as it can be used to calculate how long the drug may persist in the body once dosing has ceased and how long it will take before dosing adjustments reach steady state. A commonly used rule of thumb is that a timespan of five half-lives will essentially eliminate the majority of a drug (~3 percent remaining).

In 1973, Sir Colin Dollery, one of the grand masters in the field of clinical pharmacology, commented that the study of PK alone is not an end in itself and that it is the action of the drug that counts. When designing our clinical programs and providing labeling information to guide patients and their prescribers, CPTR colleagues endeavor to provide data that are useful and can inform treatment decisions. The PK half-life of a drug may have some descriptive value, but more important, it is the dose and dose frequency that determine drug action. When communicating the characteristics of a drug, we are attempting to synthesize all our knowledge of the drug.

Typically the patient is most interested in how quickly the benefit of the drug will be noticed. While knowledge of the drug’s PK can inform this assessment, usually the clinical pharmacologist will try to link the PK to some measure of activity or a biomarker of clinical effect. Using mathematical modeling, quantitative links between dose/concentration and effect are sought. Often these relationships are described by nonlinear equations, observing a maximum effect and a dose/concentration that achieves half of this effect. In these situations, the PK half-life may not be a particularly helpful metric. The pharmacodynamic (PD) effect of a drug will be a function of dose, dosing interval, and its intrinsic potency. Patients and their prescribers are most likely to care about duration of effect. Unfortunately a PD half-life equivalent of PK half-life does not typically have any meaningful utility, due to the inherent nonlinearity in the system. In these situations, it is more helpful to discuss the minimum dose/concentration at which a drug response is seen, to better inform choice of dose.

In the December issue of the AAPS Newsmagazine, we describe how the term half-life has broad applicability and is useful for describing many of the phenomena we observe in the world of pharmaceuticals today. Read The Meaning of (Half)-Life, from the CPTR section, and then participate in the discussion point below.

Is half-life a useful parameter to help describe the properties of your drugs? If not, why not, and what do you use instead?

John D. Davis, Ph.D., is head of clinical pharmacology at Regeneron Pharmaceuticals in Tarrytown, NY. He has worked for Medeval Ltd., Pfizer, and most recently for Genentech, and he is currently secretary-treasurer of the Clinical Pharmacology & Translational Research section of AAPS.