Pharmacokinetic tool and method for predicting metabolism of a compound in a mammal

• US 20040039530A1
• Filed: 05/30/2003
• Published: 02/26/2004
• Est. Priority Date: 07/30/2001
• Status: Abandoned Application

• Current Assignee: Lion Bioscience AG (2invest AG)
• Original Assignee: Lion Bioscience AG (2invest AG)
• Inventors: Leesman, Glen D, Sinko, Patrick J, Doerr-Stevens, Julie, Grass, George M, Izhikevich, Tatyana, Thakker, Dhiren R, Norris, Daniel A, Lecluyse, Edward, Holme, Kevin
• Application Number:
  US10/332,996
• Publication Number:
  US 20040039530A1
• Time in Patent Office: Days
• US Class Current: 702/19
• CPC Class Codes: G16C 20/10 Analysis or design of chemical reactions, syntheses or processes
• CPC Class Codes: G16C 20/30 Prediction of properties of chemical compounds, compositions or mixtures

Abstract

A system for simulating metabolism of a compound in a mammal is disclosed that includes a metabolism simulation model of a mammalian liver. This model has equations which, when executed on a computer, calculate the rate of metabolism of the compound in the cells of the mammalian liver and a rate of transport of the compound into the cells, wherein the simulation model determines an amount of the metabolism product. The rate of metabolism may be a rate of depletion of the compound. The metabolism product may be an amount of the compound remaining after the compound'"'"'s first passage through the mammalian liver (This is not necessarily limited to first pass, nor would it need to be limited to the liver. Intestinal metabolism could also be modeled). The rate of metabolism may alternatively be a rate of accumulation of a metabolite of the compound.

Claims

1. A system for simulating metabolism of a compound in a mammal comprising:

a metabolism simulation model of a mammalian liver comprising equations which, when executed on a computer, describe a rate of metabolism of the compound in the cells of the mammalian liver and a rate of transport of the compound into the cells, wherein the simulation model determines either (a) an amount of the compound remaining after its first passage through the mammalian liver or (b) an amount of the metabolite generated as a result of the compound'"'"'s first passage through the mammalian liver.

2. The system of claim 1 wherein the model uses data collected in an animal.

3. The system of claim 1 wherein the model uses data collected from the group consisting of:

hepatocyte, microsome, S-9 fractions, other subcellular fractions, liver slice, supernatant fraction of homogenized hepatocytes, Caco-2 cells, or segment-specific rabbit intestinal tissue sections.

4. The system of claim 3 wherein the group according to claim 3 is cultured in vitro.

5. The system of claim 1 wherein the metabolism simulation model includes a model of the liver selected from the group consisting of a parallel tube model, a mixing tank model, a distributed flow model and a dispersed flow model.

6. The system of claim 1 wherein the equation describing rate of depletion/accumulation/metabolism is the Michaelis Menten equation or an equation based on the Michaelis Menten equation.

7. The system of claim 1 wherein the equation describing rate of transport is a first order transport rate constant multiplied by the concentration of the compound.

8. The system of claim 1 wherein the rate of transport is adjusted by the rate of depletion.

9. The system of claim 1 wherein the transport is modeled as a first order term that approximates a passive thermodynamic process.

10. The system of claim 1 wherein absorption rate data and matabolism data are supplied to the model.

11. The system of claim 10 wherein the metabolism data is concentration of parent compound remaining verses time.

12. The system of claim 10 wherein the absorption rate data is empirically calculated.

13. The system of claim 10 wherein the absorption rate data is estimated by an absorption simulation model.

14. A computer-implemented method for calculating an estimated parameter value for the metabolism of a compound comprising:

(a) providing a computer and a computer program;

(b) supplying to the computer program concentration of parent compound remaining versus time data for the compound at a plurality of concentrations;

(c) running the computer program under conditions in which such program (i) selects a data fitting method from a predetermined selection of data fitting methods, and (ii) uses the selected data fitting method to calculate the estimated parameter values.

15. The method of claim 14 wherein the parameter is selected from the group consisting of Vmax, Km and Kd.

16. The method of claim 14 further comprising:

(d) entering the estimated parameter value into a metabolism simulation model.

17. A computer-implemented method for calculating a parameter estimate for the metabolism of a compound comprising:

(a) providing a computer and computer program;

(b) supplying to the computer program concentration of parent compound remaining versus time data for the compound at a plurality of concentrations;

(c) running the computer program wherein such program selects (i) a subset of such data for use in the calculation of the parameter estimate, and (ii) a data fitting method for analysis of such data, using the data and data fitting methods to calculate the parameter estimate.

18. The method of claim 17 wherein such program recommends to the user (i) a subset of such data for use in the calculation of the parameter estimate, and (ii) a data fitting method for analysis of such data, and

the method further comprising:

(d) informing a user of the computer of such selections;

(e) recording the user'"'"'s acceptance or rejection of each such selection; and

(f) using the data and data fitting methods chosen by the user to calculate the parameter estimate.

19. A method of collecting data for predicting the metabolism of a compound,

said method comprising:

collecting concentration of parent compound remaining versus time data under standard assay conditions applicable to a diverse range of compounds, and wherein said diverse range of compounds includes at least one compound having a Km value below 10, at least one compound having a Km value between 10 and 100 and at least one compound having a Km value above 100.

20. The method of claim 19 wherein said collecting is performed by a machine.

21. The method of claim 20 wherein said machine is programmed to select such times and concentrations without human intervention.

22. The method of claim 21 wherein the concentration less than 10 is selected from the range from 0.2 to 4.0.

23. The method of claim 21 wherein the concentration between 10 and 100 is selected from the range from 25 to 75.

24. The method of claim 21 wherein the concentration above 100 is selected from the range from 110 to 190.

25. The method of claim 19 wherein said collecting is performed using hepatocytes.

26. The method of claim 19 wherein said collecting is performed using microsomes.

27. The method of claim 19 wherein said collecting is performed using a liver slice.

28. The method of claim 19 wherein said collecting is performed using a S9 fractions.

29. The method of claim 19 further comprising:

entering the concentration versus time data into a metabolism simulation model.

30. A method of collecting data for predicting the metabolism of a compound, said method comprising:

collecting concentration versus time data at a plurality of concentrations selected without regard to the Vmax, Km or Kd of the compound.

31. A computer-implemented method for calculating an estimated parameter value for the metabolism of a compound comprising:

(a) providing a computer and a computer program;

(b) supplying to the computer program concentration of parent compound remaining versus time data for the compound at a plurality of concentrations;

(c) running the computer program under conditions in which such program (i) chooses a subset of such data for use in the calculation of the estimated parameter value, and (ii) uses such subset of data to calculate the estimated parameter value.

32. A system for simulating metabolism of a compound in a mammal comprising:

a metabolism simulation model of a mammalian liver comprising equations which, when executed on a computer, describe a rate of accumulation of a metabolite of the compound in the cells of the mammalian liver and a rate of transport of the compound into the cells, wherein the simulation model determines either (a) an amount of the compound remaining after its first passage through the mammalian liver or (b) an amount of the metabolite generated as a result of the compound'"'"'s first passage through the mammalian liver.

33. A system for simulating metabolism of a compound in a mammal comprising:

a metabolism simulation model of a mammalian liver comprising equations which, when executed on a computer, describe a rate of depletion of the compound in the cells of the mammalian liver and a rate of transport of the compound into the cells, wherein the simulation model determines either (a) an amount of the compound remaining after its first passage through the mammalian liver or (b) an amount of the metabolite generated as a result of the compound'"'"'s first passage through the mammalian liver.

34. A method for predicting the in vivo metabolism of a compound, the method comprising:

receiving as an input concentration versus time data for the compound at a plurality of concentrations from in vitro metabolic assays;

predicting the amount of the compound metabolized based on the input data and using a model that describes the rate of depletion of the compound in a liver and the rate of transport of the compound into liver cells.

38. The invention of claims 34-37 wherein the algorithms utilize at least one adjustment parameter.

40. The invention of claims 34-37 wherein the algorithms utilize rules that determine the input data that is excluded from determining an estimated parameter value.

35. A model for predicting the in vivo metabolism of a compound, the method comprising:

means for receiving as an input concentration versus time data for the compound at a plurality of concentrations from in vitro metabolic assays;

means for predicting the amount of the compound metabolized based on the input data and using algorithms that describe the rate of depletion of the compound in a liver and the rate of transport of the compound into liver cells.

36. A model for predicting the in vivo metabolism of a compound, the method comprising:

a receiver, the receiver receiving input concentration versus time data for the compound at a plurality of concentrations from in vitro metabolic assays; and

a predictor that predicts the amount of the compound metabolized based on the input data and uses algorithms that describe the rate of depletion of the compound in a liver and the rate of transport of the compound into liver cells.

37. A computer readable medium containing a metabolism model, the model comprising:

a computer readable medium; and

a data structure on the medium that predicts the amount of the compound metabolized based on the input data and uses algorithms that describe the rate of depletion of the compound in a liver and the rate of transport of the compound into liver cells.

39. The invention of claim 37 wherein the adjustment parameter is obtained by mapping in vitro and structural data.

41. A method for developing a metabolism model, the method comprising:

obtaining in vitro metabolism assay data for a plurality of compounds;

obtaining for each compound concentration of parent compound remaining verses time data; and

generating at least one model that maps the in vitro data with the concentration of parent compound remaining verses time data.

42. A method for developing a metabolism model, the method comprising:

obtaining in vitro metabolism assay data for a plurality of compounds;

obtaining for each compound concentration of metabolite accumulation verses time data; and

generating at least one model that maps the in vitro data with the concentration of metabolite accumulation verses time data.