Predicting Human Drug Distribution

Volume of distribution is a pharmacokinetic term, derived from analysing the plasma-time curve of a drug, and is the hypothetical volume in which a drug would have to distribute to give the observed plasma concentration. It modulates the half-life of the drug with a given clearance. 

Mathematically, it can be described by the Gilette equation where volume of distribution (at steady state, Vss) is given by eqn (13.2). 

Where Vp = plasma volume Vf = tissue volume fop = fraction unbound in plasma /ut = fraction unbound in tissue. 

A more physiological approach was taken by Oie and Tozer, who expressed Vss.according to efin (13.3).  

In eqn (3),/up is the fraction unbound in plasma,is the fraction unbound in tissues and. R /zis the extravascular/intravascular ratio of binding proteins (usually 1.4 for albumin). Vp, Vp, and Vr refer to the volumes of plasma, 

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Poulin P, Chen YH, Ding X, Gould SE, Hop ECJ, Messick K, Oeh J, Liederer B. 2015a. Prediction of drug distribution in subcutaneous xenografts of human tumor cell lines and healthy tissues in mouse application of the tissue composition-based model to antineoplastic agents. J Pharm Sci 104 1508-1521. 

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

Actisomide was included in a set of drugs for computational predictions of human drug clearance using different allometry methods (08MI1, 09JPS2472) and for computational predictions of volume of distribution using linear and nonlinear models (09JMC4488). 

Poulin P, Ekins S, Theil FP (2011) A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human. Toxicol Appl Pharmacol 250(2) 194-212... 

Volume of distribution is a conceptual pharmacokinetic parameter that scales the extent of a drug distributed into the tissues. A well-known parameter, elimination half-life, can be derived from clearance and volume of distribution. It is a very important developability criterion that warrants the desired dose regimen. It should be noted here that half-life must be discussed in the context of a biologically relevant concentration. A purely mathematically derived half-life is sometimes biological irrelevant. Some more definitive explanations and comprehensive discussion of the major pharmacokinetic parameters and their biological relevance have been extensively reviewed.25,26 These parameters should be examined across several different preclinical species to predict the behavior in humans. The DMPK topics will be discussed in Chapters 5 and 6. 

Poulin P. 2015a. Drug distribution to human tissues prediction and examination of the basic assumption in in vivo pharmacokinetics-pharmacodynamics (PK/PD) research. J Pharm Sci 104 2110-2118. 

Poulin, P, Theil FP. 2009. Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods. J Pharm Sci 98 4941 961. 

Lombardo F, Obach RS, Shalaeva MY and Gao F. Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem 2002 45 2867-76. 

M. Y., Gao, F. Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics. J. Med. Chem. 2004, 47,1242-1250. 

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