Pharmacokinetic-based drug design tool and method

A computer-implemented method of optimizing a model for predicting an in vivo property of a compound in a mammalian system of interest, the method comprising:

• (i) providing a computer containing the model;
• (ii) assigning an initial value to a selected adjustment parameter of the model;
• (iii) inputting first data for a plurality of compounds into the model on the computer to generate output data;
• (iv) comparing the output data with second data for the plurality of compounds;
• (v) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iv) is reduced;
• and
• (vi) replacing the value for the selected adjustment parameter in the model with the new value selected in step (v).

A computer-implemented method of generating optimized values for adjustment parameters of a physiologic-based model, the model predicting an in vivo property of a compound in a mammalian system of interest from an in vitro property of the compound, the method comprising:

• (i) providing a computer having a curve-fitting algorithm and the physiologic-based model of the mammalian system of interest, the model comprising two or more equations, the model having as an output a predicted in vivo property of a compound in the mammalian system as a function of time, and at least two of the two or more equations are each modified by at least one adjustment parameter;
• (ii) assigning an initial value to each of a plurality of adjustment parameters of the model;
• (iii) inputting data from a first data source into the model and running the model to generate output data, the first data source containing first data for a plurality of compounds;
• (iv) comparing the output data with a second data source, the second data source containing second data for the plurality of compounds;
• (v) selecting a new value for one or more of the plurality of adjustment parameters such that deviation of the comparison in step (iv) is reduced using at least the curve-fitting algorithm on the computer;
• and
• (vi) replacing the value for the one or more of the plurality of adjustment parameters in the model with the new value selected in step (v).

A computer-implemented method of generating optimized values for a plurality of selected adjustment parameters of a physiologic-based model, the model predicting an in vivo property of a compound in a first mammalian system from an in vivo property of the compound in a second mammalian system, the method comprising:

• (i) providing a computer having a curve-fitting algorithm and the physiologic-based model of the first mammalian system, the model having as an output an in vivo property of a compound in the first mammalian system as a function of time, and wherein the model comprises the plurality of selected adjustment parameters;
• (ii) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (iii) inputting data from first data for a plurality of compounds into the model and running the model to generate output data, the first data containing in vivo data for each of a plurality of compounds in the second mammalian system;
• (iv) comparing the output data with second data containing in vivo data for each of the plurality of compounds in the first mammalian system;
• (v) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iv) is reduced using at least the curve-fitting algorithm on the computer;
• and
• (vi) replacing the value of the one or more of the plurality of selected adjustment parameters in the model with the new value selected in step (v).

A computer implemented method of generating a selectively optimized adjustment parameter of a physiologic pharmacokinetic model of a mammalian system of interest that corresponds to a second species of mammal for predicting a pharmacokinetic property of a compound in the mammalian system from in vivo data obtained from a first species of mammal, the method comprising:

• (i) providing a computer having a physiologic pharmacokinetic model of the mammalian system of interest, the model calculates as one or more output variables a pharmacokinetic property of a compound in the mammalian system as a function of time, wherein the model comprises a selected adjustment parameter;
• (ii) assigning an initial value to the selected adjustment parameter of the model;
• (iii) inputting data from a first data source into the model and running the model to generate output data, the first data source containing the first data for a plurality of compounds;
• (iv) comparing the output data with a second data source, the second data source containing data for the plurality of compounds in the mammalian system of interest;
• (v) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iv) is reduced using at least the curve-fitting algorithm on the computer;
• and
• (vi) replacing the value of the selected adjustment parameter in the model with the new value selected in step (v).

A computer-implemented method for optimizing a physiologic pharmacokinetic model for predicting a pharmacokinetic property of a compound in a mammalian system of interest, the method comprising:

• (i) providing a computer having a curve-fitting algorithm and the physiologic pharmacokinetic model of the mammalian system of interest, the model having as an output an in vivo property of a compound in the mammalian system as a function of time, and wherein the model comprises a plurality of selected adjustment parameters;
• (ii) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (iii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iv) comparing the output data with second data for the plurality of compounds in the mammalian system of interest;
• (v) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iv) is reduced using at least the curve-fitting algorithm on the computer;
• and
• (vi) replacing the value for the one or more of the plurality of selected adjustment parameter values in the model with the new value selected in step (v).

A device for selectively optimizing a model for predicting a pharmacokinetic property of a compound in a mammalian system of interest, the device comprising:

• assigning means for assigning an initial value to a selected adjustment parameter;
• inputting means for inputting first data for a plurality of compounds into the model;
• running means for running the model to generate output data;
• comparing means for comparing the output data with second data for the plurality of compounds;
• selecting means for selecting a new value for the selected adjustment parameter such that deviation of the comparison from the comparison means is reduced;
• and
• replacing means for replacing the value of the selected adjustment parameter in the model with the new value selected by the selecting means.

A method for predicting a pharmacokinetic property of a compound in a mammalian system of interest, the method comprising:

• providing a model, wherein the model comprises a selected adjustment parameter and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the selected adjustment parameter in the model with the new value selected in step (iv);
• and
• using the model to predict a pharmacokinetic property of a particular compound.

An article of manufacture comprising:

• a computer readable medium;
• and
• a data structure stored on the medium for predicting a pharmacokinetic property of a compound in a mammal of interest, wherein the data structure comprises a computer readable model of a selected mammalian system, wherein the computer readable model comprises a selected adjustment parameter, and wherein the data structure further comprises a value obtained by means for:
• (i) assigning an initial value to the selected adjustment parameter of the model;
• (ii) receiving first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in (iii) is reduced;
• and
• (v) replacing the value of the selected adjustment parameter in the model with the new value selected in (iv).

A computer program product for predicting a pharmacokinetic property of a compound in a mammal, the product comprising:

• a computer readable medium;
• and
• a program stored on the medium for predicting a pharmacokinetic property of a compound in a mammal of interest, wherein the program comprises a computer readable model of a selected mammalian system, the computer readable model comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises values obtained by:
• (i) assigning an initial value to the selected adjustment parameter of the model;
• (ii) inputting data from first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with data from second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the selected adjustment parameter in the model with the new value selected in step (iv).

An article of manufacture for predicting a pharmacokinetic property of a compound in a mammal comprising:

• a computer readable medium;
• and
• a program stored on the medium for predicting a pharmacokinetic property of a compound in a mammal, wherein the program comprises a computer readable model of a selected mammalian system, the computer readable model comprising a plurality of selectively optimized adjustment parameters, and wherein the selectively optimized adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• (v) replacing the value for one or more of the plurality of selected adjustment parameter values in the model with the new value selected in step (iv).

An article of manufacture comprising:

• a computer readable medium;
• and
• a program stored on the medium for predicting a pharmacokinetic property of a compound in a mammal of interest, wherein the program comprises a computer readable model of a selected mammalian system, the computer readable model comprises at least one selected adjustment parameter, and wherein at least the one selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the at least one selected adjustment parameter of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the at least one selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• (v) replacing the value for the at least one selected adjustment parameter in the model with the new value selected in step (iv).

An article of manufacture comprising:

• a computer readable medium;
• and
• a program stored on the medium for predicting absorption of a compound in a mammal of interest, wherein the program comprises a computer readable model of a selected mammalian system, wherein the computer readable model comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter of the model;
• (ii) inputting data first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the selected adjustment parameter in the model with the new value selected in step (iv).

A computer system for predicting a pharmacokinetic property of a compound in a mammalian system of interest, the computer system comprising:

• a computer;
• and
• a program implementing a physiologic pharmacokinetic model on the computer, wherein the model comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for of the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value for the selected adjustment parameter in the model with the new value selected in step (iv).

A method of predicting a pharmacodynamic or pharmacokinetic property of a compound in a mammal, the method comprising:

• providing a model, wherein the model comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value for the selected adjustment parameter in the model with the new value selected in step (iv);
• and
• using the model to predict the property of the compound.

A computer system for predicting absorption of a compound in a mammalian system of interest, the computer system comprising:

• a computer;
• and
• a program implementing an absorption model on the computer, wherein the model comprises at least one selected adjustment parameter and wherein the at least one selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the at least one selected adjustment parameter of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the at least one selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the at least one selected adjustment parameter value in the model with the new value selected in step (iv).

A computer system for predicting oral absorption of a compound in a mammal, the computer system comprising:

• a computer;
• and
• a program implementing an oral absorption model on the computer, wherein the model comprises a plurality of selected adjustment parameters, and wherein the plurality of selected adjustment parameters comprise values obtained by:
• (i) assigning an initial value the selected adjustment parameter of the model;
• (ii) inputting first data source containing first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the one or more of the plurality of selected adjustment parameters in the model with the new value selected in step (iv).

A computer system for predicting a property of a compound in a mammalian system, the computer system comprising:

• a computer;
• and
• a program on the computer, wherein the program comprises a plurality of selectively optimized adjustment parameters, the selectively optimized adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the program;
• (ii) inputting first data for a plurality of compounds into the program and running the program to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the one or more of the plurality of selected adjustment parameters in the program with the new value selected in step (iv).

A method of predicting a pharmacokinetic property of a compound in a mammalian system of interest, the method comprising:

• providing a computer comprising an input system, an output system and a model, wherein the model comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• (v) replacing the value for the selected adjustment parameter with the new value selected in set (iv);
• entering through the input system input data for the compound;
• using the model to predict the pharmacokinetic property of the compound;
• and
• outputting a predicted pharmacokinetic property of the compound with the output system.

A computer system for predicting a property of a compound in a mammalian system of interest, the computer system comprising:

• a computer;
• and
• a program on the computer, wherein the program comprises a selected adjustment parameter, and wherein the selected adjustment parameter comprises a value obtained by:
• (i) assigning an initial value to the selected adjustment parameter of the program;
• (ii) inputting first data for a plurality of compounds into the program and running the program to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for the selected adjustment parameter such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the selected adjustment parameter in the program with the value selected in step (iv).

A computer-implemented model of the gastrointestinal tract of a mammal for predicting a pharmacokinetic property of a compound in the mammal, the model comprising:

• a computer;
• and
• a program implementing a physiologic model on the computer, wherein the physiologic model comprises a plurality of selected adjustment parameters, and wherein the plurality of selected adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (ii) inputting data from first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with data from second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the one or more of the plurality of the selected adjustment parameters in the model with the new value selected in step (iv),
• wherein the physiologic model comprises a compartment-flow model for calculating time-dependent rate of absorption, extent of absorption, and concentration of a compound at a sampling site across a physiological barrier of one or more segments of the mammalian system, wherein
• the compartments are characterized by fluid volume, fluid absorption, insoluble mass, soluble mass, and mass absorption for one or more of segments of the GI tract of a mammal, the compartments are operably linked through flow regulators and converters, the flow regulators regulate flow among compartments and the converters modify the flow regulators, and wherein the flow regulators are characterized by fluid absorption rate, fluid transit rate, insoluble mass transit rate, insoluble mass dissolution rate, soluble mass transit rate, and soluble mass absorption rate.

A device for predicting a pharmacokinetic property of a compound in a mammalian system of interest, the device comprising:

• modeling means for modeling at least one pharmacokinetic property of a compound in a mammal, wherein the modeling means comprises adjustment means for adjusting the model, and wherein the adjustment means is obtained by:
• (i) assigning an initial value to the adjustment means;
• (ii) inputting first data for a plurality of compounds into the modeling means and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• and
• (iv) selecting a new adjustment means such that deviation of the comparison means in step (iii) is reduced;
• and
• applying means for applying the modeling means to predict a pharmacokinetic property of the compound.

A method of predicting a pharmacokinetic property of a compound in a mammalian system of interest, the method comprising:

• providing a computer comprising an input system, an output system, a processor and an absorption model, wherein the model comprises a plurality of selected adjustment parameters, and wherein the selected adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value for the one or more at the plurality of adjustment parameters in the model with the new value selected in step (iv);
• entering through the input system input data for the compound;
• using the model to predict the absorption of the compound;
• and
• outputting an absorption property of the compound with the output system.

A method for predicting solubility of a compound in the gastrointestinal (GI) tract of a mammal, the method comprising:

• providing a solubility model, wherein the solubility model is a compartment-flow model, the model comprises a plurality of selected adjustment parameters, and wherein the selected adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value for the one or more of the plurality of the selected adjustment parameters in the model with the new value selected in step (iv), wherein
• the compartments are characterized by insoluble mass and soluble mass for stomach, duodenum, jejunum, ileum and colon that are operably linked through flow regulators and one or more converters that modify one or more of the flow regulators, wherein the flow regulators are characterized by insoluble mass transit rate, insoluble mass dissolution rate, and soluble mass transit rate, wherein the converters are characterized by insoluble mass, insoluble mass transit rate constant, insoluble mass dissolution rate constant, soluble mass, and soluble mass transit rate constant, and wherein one or more of the converters are characterized by the selected adjustment parameters;
• and
• using the solubility model to predict solubility of a particular compound.

A method for predicting absorption of a compound in the gastrointestinal (GI) tract of a mammal to at least the portal vein, the method comprising:

• providing an absorption model, the absorption model corresponding to a compartment-flow model, wherein the model comprises a plurality of selected adjustment parameters, and wherein the plurality of selected adjustment parameters comprise values obtained by:
• (i) assigning an initial value to each of the plurality of selected adjustment parameters of the model;
• (ii) inputting first data for a plurality of compounds into the model and running the model to generate output data;
• (iii) comparing the output data with second data for the plurality of compounds;
• (iv) selecting a new value for one or more of the plurality of selected adjustment parameters such that deviation of the comparison in step (iii) is reduced;
• and
• (v) replacing the value of the one or more of the plurality of the selected adjustment parameters in the model with the new value selected in step (iv), wherein
• compartments in the model are characterized by soluble mass and soluble mass absorption for stomach, duodenum, jejunum, ileum and colon that are operably linked through flow regulators and one or more converters that modify the flow regulators, where the flow regulators are characterized by insoluble mass transit rate, insoluble mass dissolution rate, soluble mass transit rate, soluble mass absorption rate, where the converters are characterized by insoluble mass, insoluble mass dissolution rate constant, soluble mass transit rate constant, surface area, dissolved mass concentration, and permeability, and wherein one or more of the converters are modified by one or more of the plurality of selected adjustment parameters;
• and
• using the absorption model to predict the absorption of a particular compound.