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Prediction of Human Pharmacokinetics

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Abstract

The prediction of human pharmacokinetics is an extremely difficult endeavor during the selection of drug candidates for further human clinical testing. Despite a variety of available in vitro and in vivo methodologies, successful predictions are still difficult when performing them prospectively. This chapter gives a general overview of in vitro and in vivo methodologies used to predict human pharmacokinetics.

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Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

BrW:

Brain weight

CLhepatic :

Hepatic clearance

CLint :

Intrinsic clearance

CLu :

Unbound clearance

F :

Bioavailability

F a :

Fraction absorbed from the intestine

F g :

Fraction that escapes intestinal metabolism

F h :

Fraction that escapes hepatic metabolism

f u :

Unbound fraction in blood/plasma

f umic :

Unbound fraction in microsomes

f ut :

Unbound fraction in tissues

HPGL:

Hepatocytes per gram of liver

IVIVE:

In vitro–in vivo extrapolation

K m :

Michaelis–Menten constant (i.e., substrate concentration when v is ½ of V max)

MLP:

Maximum life span

MPPGL:

Microsomal protein per gram of liver

MRT:

Mean residence time

P450:

Cytochrome P450

PBPK:

Physiologically based pharmacokinetic model

PK:

Pharmacokinetic

P microsome :

Amount of microsomal protein in the incubation

Q :

Hepatic blood flow

R e/I :

Ratio of binding proteins in extracellular fluid (except plasma) to binding proteins in plasma

t 1/2(in vitro) :

In vitro half-life

V d :

Volume of distribution

V d,u :

Unbound volume of distribution

V e :

Extracellular fluid volume

V incubation :

Incubation volume

V max :

Maximum rate of the metabolic reaction

V p :

Plasma volume

V r :

“Remainder” of the fluid volume

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Authors and Affiliations

  1. Genentech, Inc., 1 DNA Way, San Francisco, California, USA

    Siamak Cyrus Khojasteh, Harvey Wong & Cornelis E. C. A. Hop

Authors
  1. Siamak Cyrus Khojasteh
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  2. Harvey Wong
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  3. Cornelis E. C. A. Hop
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Correspondence to Siamak Cyrus Khojasteh .

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Khojasteh, S.C., Wong, H., Hop, C.E.C.A. (2011). Prediction of Human Pharmacokinetics. In: Drug Metabolism and Pharmacokinetics Quick Guide. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5629-3_7

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