Treatment methods having reduced drug-related toxicity and methods of identifying the likelihood of patient harm from prescribed medications
Methods of determining whether specific drugs or patients carry an increased risk of causing or developing, respectively, long QT syndrome or Torsades de Pointes and methods of treating such patients.
1. A method for determining whether a medication is associated with an increased risk of drug-induced long QT syndrome or Torsades de Pointes in combination with at least one other drug by determining a drug-specific index for the medication, the method comprising the steps of:
(i) calculating a first index variable by determining;
an IC 50 value for block of one or more of I Kr and I Ks ,
a Cmax of the medication at a test dose,
a daily dose amount of the medication,
a protein binding value for the medication at a target protein,
a drug-drug interaction coefficient (DDIC) for the medication, and
calculating a value for the first index variable based on the following equation:
(
IC
50
of
I
Kr
or
I
Ks
block
)
×
1000
(
(
C
max
Dose
Test
)
×
100
-
Protein
Binding
%
100
)
×
(
Daily
Dose
Administered
(
µmoles
)
Dose
Test
(
µ
mole
)
×
DDIC
)
;
(ii) calculating a second index variable by determining:
an IC 50 value for block of CaV1.2 current,
the IC 50 value for block of one or more of I Kr and I Ks , and
calculating a value for the second index variable based on the following equation:
IC
50
for
block
of
CaV
1.2
current
IC
50
for
lock
of
I
Kr
or
I
Ks
;
(iii) calculating a third index variable by determining:
an IC 50 value for block of NaV1.5 current,
the IC 50 value for block of one or more of I Kr and I Ks , and
calculating a value for the third index variable based on the following equation:
IC
50
for
block
of
NaV
1.5
current
IC
50
for
block
of
I
Kr
or
I
Ks
;
(iv) calculating a value for a fourth index variable based on whether the medication is an inhibitor of hERG trafficking; and
(v) combining the values for the first, second, third, and fourth index variables to provide the drug-specific index, wherein a drug-specific index of less than a predetermined threshold value is indicative of an increased risk of drug-induced long QT syndrome or Torsades de Pointes for the medication in combination with the at least one other drug.
2. The method of claim 1 , wherein the medication is selected from the group consisting of Albuterol, Alfuzosin, Amantadine, Amiodarone, Amitriptyline, Amphetamine, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bepridil, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Desipramine, Dexmethylphenidate, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine, Erythromycin, Escitalopram, Escitalopram, Famotidine, Felbamate, Fenfluramine, Flecamide, Fluconazole, Fluoxetine, Foscarnet, Fosphenyloin, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol, Ibutilide, Imipramine, Indapamide, Isoproterenol, Isoproterenol, Isradipine, Itraconazole, Ketoconazole, Lapatinib, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone, Methylphenidate, Midodrine, Moexipril/HCTZ, Moxifloxacin, Nicardipine, Nilotinib, Norepinephrine, Nortriptyline, Octreotide, Ofloxacin, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Probucol, Procainamide, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Ranolazine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol, Sertindole, Sertraline, Sibutramine, Solifenacin, Sotalol, Sparfloxacin, Sunitinib, Tacrolimus, Tamoxifen, Telithromycin, Terbutaline, Terfenadine, Thioridazine, Tizanidine, Tolterodine, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Venlafaxine, Voriconazole, Ziprasidone, and a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the predetermined threshold value has a value of 15.
4. The method of claim 1 , wherein the value of the second index variable is derived such that:
a value of less than 1 yielded by the equation for calculating the second index variable yields a second index variable value of 10;
a value of between 1 to less than 5 yielded by the equation for calculating the second index variable yields a second index variable value of 5; and
a value of between 5 and less than 10 yielded by the equation for calculating the second index variable yields a second index variable value of 2.
5. The method of claim 1 , wherein the value of the third index variable is derived such that:
a value of less than 1 yielded by the equation for calculating the third index variable yields a third index variable value of 10;
a value of between 1 to less than 5 yielded by the equation for calculating the third index variable yields a third index variable value of 5; and
a value of between 5 and less than 10 yielded by the equation for calculating the third index variable yields a third index variable value of 2.
6. The method of claim 1 , wherein the value of the fourth index variable is −5 if the medication is an inhibitor of hERG trafficking, and the fourth index variable is 0 if the medication is not an inhibitor of hERG trafficking.
7. The method of claim 1 , wherein the predetermined threshold value has a value of 10.