METHODS OF REDUCTION OF INTERPATIENT VARIABILITY
Disclosed herein are methods for the reduction of inter-patient variability of a drug, such as in one or more parameters including half-life (t 1/2 ), maximum plasma concentration (C max ), time at maximal plasma concentration (T max ), area under the time-versus-concentration curve (AUC). Also provided are methods of reducing side effects associated with drugs.
1 . A method of reducing inter-patient variability in a drug treatment, comprising;
i. identifying inter-patient variability in said drug treatment;
ii. preparing a deuterated analog of said drug; and
iii. using said deuterated analog in said drug treatment to reduce inter-patient variability of said drug treatment.
2 . The method as recited in claim 1 wherein said deuterated analog has deuteration at one or more sites metabolized by a cytochrome P 450 .
3 . The method as recited in claim 2 wherein said cytochrome P 450 is a polymorphically expressed cytochrome P 450 .
4 . The method as recited in claim 3 wherein said polymorphically expressed cytochrome P 450 is selected from the group consisting of CYP3A4, CYP2D6 and CYP2C19.
5 . The method as recited in claim 1 wherein said interpatient variability is in the frequency or severity of side effects experienced.
6 . The method as recited in claim 1 wherein said interpatient variability is in the half-life (t 1/2 ) of a drug in the plasma.
7 . The method as recited in claim 1 wherein said interpatient variability is in the maximum plasma concentration (C max ) of a drug in the plasma.
8 . The method as recited in claim 1 wherein said interpatient variability is in the time at maximal plasma concentration (T max ) of a drug in the plasma.
9 . The method as recited in claim 1 wherein said interpatient variability is in the area under the time-versus-concentration curve (AUC) of a drug in the plasma.
10 . The method as recited in claim 1 wherein said interpatient variability is in the metabolite profile of the drug.
11 . The method as recited in claim 1 wherein said drug is venlafaxine.
12 . The method as recited in claim 11 wherein using said deuterated analog yields a reduced inter-patient variability in plasma half life (t 1/2 ) of 20% or more compared to non-deuterated venlafaxine.
13 . The method as recited in claim 11 wherein using said deuterated analog yields a reduced inter-patient variability in maximum plasma concentration (C max ) of 30% or more compared to non-deuterated venlafaxine.
14 . The method as recited in claim 11 wherein using said deuterated analog yields a reduced inter-patient variability in time at maximal plasma concentration (T max ) of 15% or more compared to non-deuterated venlafaxine.
15 . The method as recited in claim 11 wherein using said deuterated analog yields a reduced inter-patient variability in plasma area under the time-versus-concentration curve (AUC) of 20% or more compared to non-deuterated venlafaxine.
16 . The method as recited in claim 11 wherein using said deuterated analog yields a reduction in the incendence of one or more side effects.
17 . The method as recited in claim 16 wherein using said deuterated analog yields at least 25% fewer side effects overall than non-deuterated venlafaxine.
18 . The method as recited in claim 16 wherein the side effect is selected from the group consisting of drowsiness, dry mouth, fatigue or somnolence, headache, lightheadedness, nausea, emesis, mydriasis, anxiety, nervousness, and insomnia, dizziness, anxiety, asthenia, sweating, anorexia, weight gain, activation of mania/hypomania, and suicidal ideation.
19 . A method of reducing interpatient variability in a population of patients taking a drug comprising
i. identifying a population of patients having interpatient variability; and
ii. administering to a population of patients a deuterated analog of a drug.
20 . A deuterated analog of venlafaxine having a reduced inter-patient variability in plasma half life of 20% or more compared to non-deuterated venlafaxine.
21 . A deuterated analog of venlafaxine having a reduced inter-patient variability in maximum plasma concentration in humans of 30% or more compared to non-deuterated venlafaxine.
22 . A deuterated analog of venlafaxine having a reduced inter-patient variability in maximum plasma concentration in humans of 40% or more compared to non-deuterated venlafaxine.
23 . A deuterated analog of venlafaxine having a reduced inter-patient variability time at maximal plasma concentration in humans of 15% or more compared to non-deuterated venlafaxine.
24 . A deuterated analog of venlafaxine having a reduced inter-patient variability in plasma area under the time-versus-concentration curve 20% or more compared to non-deuterated venlafaxine.
25 . A deuterated analog of venlafaxine which causes at least 25% fewer side effects than non-deuterated venlafaxine.