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Method and apparatus for assaying a drug candidate to estimate a pharmacokinetic parameter associated therewith

a drug candidate and parameter technology, applied in the field of method and apparatus for assaying a drug candidate, can solve the problems of difficult to accurately predict the pharmacological effect of promising new drug candidates, limited number of useful models, and difficult experimentally obtained information to adequately describe such pharmacokinetic physiologic models

Inactive Publication Date: 2005-02-17
GE HEALTHCARE BIO SCI CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In brief, the present invention is directed to a method and apparatus for assaying a drug candidate. More specifically, this invention discloses a method for measuring the binding interaction between a drug candidate and sensing surface-bound biomolecules of a biosensor to determine a binding inte

Problems solved by technology

Because the body delays the transport of drug molecules across membranes, dilutes them into various compartments of distribution, transforms them into metabolites, and eventually excretes them, it is often difficult to accurately predict the pharmacological effect of promising new drug candidates.
In general, however, the number of useful models is limited due to practical considerations associated with blood, tissue and / or organ sampling.
Unfortunately, much of the information required to adequately describe such pharmacokinetic physiologic models are often very difficult to obtain experimentally.

Method used

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  • Method and apparatus for assaying a drug candidate to estimate a pharmacokinetic parameter associated therewith
  • Method and apparatus for assaying a drug candidate to estimate a pharmacokinetic parameter associated therewith
  • Method and apparatus for assaying a drug candidate to estimate a pharmacokinetic parameter associated therewith

Examples

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example 1

Simultaneous Measurement of Solubility, Plasma Protein Binding Lipophilicity and Intestinal Absorption for Three Drug Candidates A-C

This example discloses how combined information from each of four different flow-cells of a biosensor may be represented in a characterization matrix where each of the three drug candidates A-C illustrates a quality pattern (i.e., HSA % Bound, Predicted Lipophilicity, Solubility, and Predicted FA %) which is useful for the selection of lead drug compounds.

Preparation of Sensor Chip

Three of the four discrete sensing surfaces of a CM5 Sensor Chip (Biacore AB, Uppsala, Sweden) were modified such that the CM5 Sensor Chip had surface-bound biomolecules as depicted below in Table 1.

TABLE 1SURFACE-BOUND BIOMOLECULES OF CM5 SENSOR CHIPType ofSurface / Cell No.Flow-CellSurface ModificationFC1Ref-1Unmodified carboxymethyl dextran (CM5)FC2Target-1Human Serum albumin - HSA (9-12 kRU)FC3Target-2DMPC-liposomes (5-7 kRU) captured onstearylamineFC4Target-3POPC-li...

example 2

Demonstrated Correlation Between Biosensor Data and Fraction Absorbed in Humans (FA %)

This example discloses a correlation between biosensor data obtained form the BIACORE instrument (i.e., BIACORE 3000) and known data for the fraction absorbed in humans (FA %) for a number of different drugs, wherein the correlation graph is useful for drug candidate absorption predictions. More specifically, a correlation graph as shown in FIG. 7 was constructed having known fraction absorbed in humans (FA %) plotted along the ordinate (i.e., the y-axis) and corresponding calibrated (i.e., reference subtracted) steady state binding levels for each drug at 500 μM plotted along the abscissa in a 10-logarithm scale (i.e., the x-axis). In this example, the sensing surfaces of the target flow-cells each had 6,000 RU of POPC-GM3 ganglioside (available from Sigma) captured on stearylamine tiles. (Note that an unmodified sensing surface of a CM5 Sensor Chip was used as the reference.) As shown in FIG. 7...

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Abstract

A method and apparatus for assaying a drug candidate with a biosensor having one or more sensing surface-bound biomolecules associated therewith are disclosed. The method comprises the steps of measuring the binding interaction between the drug candidate and the one or more sensing surface-bound biomolecules of the biosensor to obtain an estimate of at least one binding interaction parameter of the drug candidate, and then comparing the estimated binding interaction parameter against a mathematical expression correlated from binding interaction data associated with known drug compounds to determine an estimate of at least pharmacokinetic parameter of absorption, distribution, metabolism, or excretion (ADME) that is related to the drug candidate. The present invention allows for the simultaneous measurement of different pharmacokinetic parameters of the drug candidate, as well as an indication of the drug candidate's solubility, by use of a single analytical instrument. The pharmacokinetic data may be represented as a ADME characterization profile; such ADME profiles are of great utility for purposes of drug screening and lead optimization.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention This invention is generally directed to a method and apparatus for assaying a drug candidate and, more specifically, to a method for measuring the binding interaction between a drug candidate and sensing surface-bound biomolecules of a biosensor to determine a binding interaction parameter of the drug candidate, and then comparing the binding interaction parameter against a predetermined drug correlation graph (e.g., a mathematical expression) to estimate at least one pharmacokinetic parameter. 2. Description of the Related Art A variety of experimental techniques are currently used to determine chemical, physical and biological properties associated with low molecular weight substances, particularly in the context of drug discovery. For example, researchers are often concerned with determining a variety of chemical, physical and biological properties associated with drug candidates for screening purposes. The determination o...

Claims

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Application Information

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IPC IPC(8): G01N21/05G01N21/27G01N33/15G01N33/483G01N33/543G01N33/50G01N33/94
CPCG01N33/54373Y10S436/805G01N33/94
Inventor HAMALAINEN, MARKKUKARLSSON, ROBERTLOFAS, STEFAN
Owner GE HEALTHCARE BIO SCI CORP
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