Optimization and individualization of medication selection and dosing
The invention provides population models, methods, and algorithms for targeting a dosing regimen or compound selection to an individual patient. The methods and algorithms of the invention utilize population models that incorporate genotype information for genes encoding drug metabolizing enzymes for one or more compounds of interest. The methods allow integration of genotype information for one or more genes encoding a drug metabolizing enzyme, particularly a cytochrome P450 gene with patient data. The methods allow integration of genotype information and the effect of one or more compounds on one or more drug metabolizing enzymes. The methods allow iterative feedback of drug metabolizing data obtained from a patient into the process of generating a dosage regimen recommendation for a compound of interest for an individual patient.
1. A method for determining a starting dose of a neuropsychiatric drug for administration to a patient in need thereof, the method comprising:
(a) receiving at a processor the usual drug dose for the population representing the patient (Dpop);
(b) receiving at a processor the patient's genotype for a panel of genes comprising the following cytochrome P450 (CYP) genes: CYP2D6, CYP2C19, and CYP2C9;
(c) determining the number of functional and non-functional alleles for each gene based on said genotype;
(d) assigning the patient into a metabolizer phenotype subgroup based upon the number of functional alleles for each of the CYP genes wherein the metabolizer subgroup is selected from one of the following:
Extensive metabolizer (EM)=2 functional alleles,
Intermediate metabolizer (IM)=1 functional allele, and
Poor metabolizer (PM)=0 functional alleles;
(e) receiving at a processor the frequency of the metabolizer phenotype subgroups in the population;
(f) determining, via a processor, the starting dose of the drug expressed as a percentage based on the number of non-functional alleles as follows:
Percent reduction for one non-functional allele:
(DREM %−DRIM %)/DREM %
Percent reduction for two non-functional alleles:
(DREM %−DRPM %)/DREM %
wherein DRX % is the dosing recommendation for metabolizer subgroup X expressed as a percentage of the usual drug dose (Dpop),
wherein DEM is reduced by 20% for every non-functional CYP2D6 or CYP2C19 allele and by 40% for every non-functional CYP2C9 allele, and
(g) administering the starting dose of the drug determined in step (f) to the patient.
2. The method of claim 1 , wherein the usual drug dose (Dpop) is reduced by
20% for every non-functional CYP2D6 allele detected in said patient and the drug is selected from the group consisting of atomoxetine, imipramine, perphenazine, doxepin, maprotiline, trimipramine, thioridazine, desipramine, clomipramine, zuclopenthixol, paroxetine, venlafaxine, flupentixol, and mianserin;
20% for every non-functional CYP2C19 allele detected in said patient and the drug is selected from the group consisting of trimipramine, amitryptiline, moclobemide, imipramine, citalopram, clomipramine, and fluoxetine; and
40% for every non-functional CYP2C9 allele detected in said patient and the drug is selected from the group consisting of glimepiride, glipizide, glyburide, losartan, hydrochlorothiazide, chlorpropamide, tolbutamide, tolazamide, and warfarin.
3. The method of claim 1 or 2 , wherein the panel of genes in step (b) further comprises one or more genes selected from the group consisting of CYP1A2, CYP2E1, a serotonin transporter gene, a serotonin receptor gene, a dopamine transporter gene and a dopamine receptor gene.
4. The method of claim 3 , wherein the alleles of for each gene are selected from the group consisting of CYP1A2*1A, CYP1A2*3, CYP2C19*1A, CYP2C19*1B, CYP2C19*2A, CYP2D6*1A, CYP2D6*2, CYP2D6*2N, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*12, or CYP2D6*17.
5. The method of claim 3 , wherein said serotonin receptor gene encodes serotonin receptors 1A, 1B, 1D, 2A, or 2C.
6. The method of claim 3 , wherein said dopamine receptor gene encodes dopamine receptors D1, D2, D3, D4, D5 or D6.