To scale or not to scale: the principles of dose extrapolation - PubMed (original) (raw)

Review

To scale or not to scale: the principles of dose extrapolation

Vijay Sharma et al. Br J Pharmacol. 2009 Jul.

Abstract

The principles of inter-species dose extrapolation are poorly understood and applied. We provide an overview of the principles underlying dose scaling for size and dose adjustment for size-independent differences. Scaling of a dose is required in three main situations: the anticipation of first-in-human doses for clinical trials, dose extrapolation in veterinary practice and dose extrapolation for experimental purposes. Each of these situations is discussed. Allometric scaling of drug doses is commonly used for practical reasons, but can be more accurate when one takes into account species differences in pharmacokinetic parameters (clearance, volume of distribution). Simple scaling of drug doses can be misleading for some drugs; correction for protein binding, physicochemical properties of the drug or species differences in physiological time can improve scaling. However, differences in drug transport and metabolism, and in the dose-response relationship, can override the effect of size alone. For this reason, a range of modelling approaches have been developed, which combine in silico simulations with data obtained in vitro and/or in vivo. Drugs that are unlikely to be amenable to simple allometric scaling of their clearance or dose include drugs that are highly protein-bound, drugs that undergo extensive metabolism and active transport, drugs that undergo significant biliary excretion (MW > 500, ampiphilic, conjugated), drugs whose targets are subject to inter-species differences in expression, affinity and distribution and drugs that undergo extensive renal secretion. In addition to inter-species dose extrapolation, we provide an overview of dose extrapolation within species, discussing drug dosing in paediatrics and in the elderly.

PubMed Disclaimer

Similar articles

Cited by

References

    1. Adolph EF. Quantitative relations in the physiological constitutions of mammals. Science. 1949;109:579–585. - PubMed
    1. Agutter PS, Wheatley DN. Metabolic scaling: consensus or controversy? Theor Biol Med Model. 2004;1:13. - PMC - PubMed
    1. Aitken MM. Species differences in pharmacodynamics: some examples. Vet Res Commun. 1983;7:313–324. - PubMed
    1. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342. - PMC - PubMed
    1. Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;59:691–704. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources