Prediction volume of distribution

There have been several reports where plasma protein binding data was used in the prediction of in vivo properties of compounds. Two papers noted that the ability to predict in vivo clearance from in vitro microsome data was greatly improved when a plasma protein binding term was included [64,65]. In another study, binding to phospholipids and human serum albumin was assessed by HPLC retention times (on IAM and HAS columns, respectively) and used to predict volume of distribution [66]. 

Predict volume of distribution (Vd) and clearance (CL) based on standard population values (eg, Table 3-1) with adjustments for factors such as weight and renal function. 

Table 8.3 In vitro plasma protein binding, in vivo volume of distribution and predicted volume of distribution in humans...

Fraction of compound X unbound in the plasma (fu) In vivo volume of distribution (1kg) Predicted volume of distribution in humans (1kg)... 

Alternately, the predicted volume of distribution and elimination rate constant or the total body clearance may be used to calculate a dose... 

A number of direct in silico models to predict volume of distribution have been published, which allow volume of distribution across species to be predicted directly from chemical structure. ... 

Table 10.3 shows the predicted volume of distribution of a single intravenous bolus dose of Compound X in man this is found by using the above equation, an in vitro estimate of protein binding data for rat and dog plasma, and the observed volumes of distribution for these two species in vivo. For man, KDhuman was predicted to be 3.48— 4.591 kg using the rat data and 3.01-5.061 kg using the dog data. 

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. 

Lobell M and Sivarajah V. In silico prediction of aqueous solubility, human plasma protein binding and volume of distribution of compounds from calculated pKa and AlogP98 values. Mol Divers 2003 7 69-87. 

The distribution of a drug in the body is largely driven by its physicochemical properties and in part for some compounds by the contribution of transporter proteins [17]. By using the Oie-Tozer equation and estimates for ionization (pfCj). plasma protein binding (PPB) and lipophilicity (log quite robust predictions for the volume of distribution at steady state (Vdss), often within 2-fold of the observed value, can be made [18]. 

Van de Waterbeemd, H. Which in vitro screens guide the prediction of oral absorption and volume of distribution Basic Clin. Pharmacol. Toxicol. 2005, 96, 152-165. 

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. 

Based on the dramatic changes in volume of distribution and the free fraction of PCP found in serum, we predict that this form of therapy has the potential to rapidly reverse the toxicity of PCP, if sufficient Fab can be administered relative to the dose of PCP, The most practical method for making large quantities of antibodies with reproducible properties is through monoclonal... 

The rat has been previously used as a model animal for in vivo study of naltrexone (72). As shown in Figures 10 and 11, after an initial burst, the naltrexone plasma levels were 1.03 0.52 ng/mL/mg injected conjugate for P(HPG/LEU)-naltrexone-14-acetate and 0.70 0.39 ng/mL/mg injected conjugate for P(HPG/LEU)-naltrexone-3-acetate for 30 days. From these in vivo data, to achieve a similar plasma level in human, a subcutaneous injection dose of 100 to 500 mg can be predicted assuming that the volume of distribution of naltrexone per kilogram of body weight is of the same magnitude for both rats and humans. 

Poulin, P. Thiel, F.-P., Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution, J. Pharm. Sci. 91, 129-156 (2002). 

Estimation of the volume of distribution in man may be carried out in a number of ways. These methods have recently been reviewed by Obach et al. [60], who carried out a wide-ranging evaluation of a large number of different ways of predicting the human pharmacokinetics of 50 compounds that entered development at Pfizer. One of the simplest methods was reported to be the most reliable. It is based on the assumption that the free-fraction of drug in the plasma in dog and human and... 

Prediction of Human Volume of Distribution Using in vivo, in vitro, and in silico Approaches... 

Predicting Human Volume of Distribution from Chemical, in vitro,... 

Predicting human volume of distribution from in silico data 482... 

Some physiological volumes are known or have been estimated. Over two decades ago, Oie and Tozer proposed a relationship between the volume of distribution of a drug and its extent of plasma and tissue binding, using various fixed values for plasma and extracellular fluid volumes [1], This equation has been utilized in some methods used for prediction of steady-state VD, which will be discussed later ... 

PREDICTING HUMAN VOLUME OF DISTRIBUTION FROM CHEMICAL, IN VITRO, AND IN VIVO DATA... 

A recent variation on the prediction of human VD using allometric scaling involves the use of what has been termed "fractal volume of distribution (vf) [7], This refers to the VD value corrected to within the bounds of actual volumes within the body - in the case of human the upper and lower bounds would be 70 1 and plasma volume, respectively. Thus, even if a compound were to have a VDSS of 1000 1, its Vf would be 69.8 1. The authors of this approach have shown that Vf scales allometrically across species better than VD [8], with the explanation that body volume and body mass are exactly scaleable across species. Animal values for Vf are calculated from VD obtained from pharmacokinetic studies using the relationship ... 

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