Genotype- or Phenotype-Based Drug Formulations

Abstract

The invention relates to a combination of two or more pharmaceutically active substances, of which at least one is a metabolic product (“metabolite”) of the other (“parent substance”), wherein in particular the dosages thereof are selected such that genotypically or phenotypically related variability in the conversion of the parent substance to the metabolite in particular individuals is compensated for.

1 . Method for preparing a fixed-dose combination pharmaceutical formulation, the fixed-dose combination pharmaceutical formulation comprising a parent substance, the action of which is dependent on the quantity or the activity of expressed protein variants, enzyme variants, receptor variants or transporter variants, and at least one metabolite thereof, and the method comprising the following steps:
 a) inputting into an input module of an organism, of its genotype or phenotype, of a parent substance and at least one metabolite of the parent substance, of an optimal reference steady-state plasma level for the parent substance for a reference genotype or reference phenotype in the case of delivery of the parent substance alone,   b) forwarding of the data from a) into a calculation module comprising a substance data module, an organism data module, a genotype data module or phenotype data module, and a physiologically based pharmacokinetic model, wherein the substance data module comprises data concerning the physicochemical and/or biochemical properties of the substance, the organism module comprises data concerning the compartments of the organism, and the genotype data module or phenotype data module comprises genotype- or phenotype-specific data,   c) automatically selecting parent substance and metabolite-specific data from the substance data module,   d) automatically selecting organism-specific data from the organism data module on the basis of input a),   e) automatically selecting genotype-specific or phenotype-specific data from the genotype data module or phenotype data module,   f) forwarding of the selected data from a) to e) into the physiologically based pharmacokinetic model,   g) calculating, by means of the physiologically based pharmacokinetic model, an optimized dosage for the parent substance for the reference genotype or reference phenotype in order to attain the inputted optimal reference plasma level for the parent substance from a),   h) calculating the reference steady-state plasma level for the metabolites for the reference genotype or reference phenotype in the case of administration of the dose of parent substance calculated in g),   i) calculating a plasma level of the metabolites that is reduced owing to the genotype or phenotype with respect to the corresponding reference plasma level in the case of administration of the dose of parent substance calculated in g),   j) calculating a metabolite dose and a parent substance dose for the combined attainment of the reference plasma level for the metabolites from h) and of the reference plasma level for the parent substance from a),   k) outputting the metabolite dose and the parent substance dose for the fixed-dose combination pharmaceutical formulation via an output module, and/or forwarding the dose calculated in j) into an automated device for dosing medicaments.   
     
     
         2 . Method according to  claim 1 , wherein the dosage is defined in a genotype- or phenotype-specific manner. 
     
     
         3 . Method according to  claim 1 , wherein the formulation comprises tamoxifen and endoxifen. 
     
     
         4 . Method according to  claim 3 , wherein the formulation comprises 15-25 mg of tamoxifen and 0.25-5.0 mg of endoxifen. 
     
     
         5 . Method according to  claim 4 , wherein the formulation is adapted for CYP2D6 IM patients and comprises 15-25 mg of tamoxifen and 0.25-2.00 mg of endoxifen. 
     
     
         6 . Method according to  claim 4 , wherein the formulation is adapted for CYP2D6 PM patients and comprises 15-25 mg of tamoxifen and 1.0-5.0 mg of endoxifen.