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. An ex vivo method for determining whether a medication is associated with an increased risk of 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
(
Cmax
Dose
Test
)
⨯
100
-
Protein
Binding
%
100
)
⨯
(
Daily
Dose
Administered
(
μmoles
)
Dose
Test
(
μmole
)
⨯
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
N
aV
1.5
current
IC
50
for
b
lock
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 long QT syndrome or Torsades de Pointes for the medication in combination with the at least one other drug.
2. An ex vivo method for determining whether a patient undergoing treatment with one or more medications has an increased risk of long QT syndrome or Torsades de Pointes by determining a patient-specific score, the method comprising:
one or more steps (a)-(g):
(a) determining a risk variable having a value between 0 and 0.5 based on the patient's gender and age;
(b) determining a risk variable having a value between 0 and 1 based on a measurement of the patient's heart rhythm, the measurement comprising detecting one or more of sinus rhythm, atrial fibrillation, sick sinus syndrome, pause, and heart rate;
(c) determining a risk variable having a value between 0 and 1 based on a detected potassium level in the patient;
(d) determining a risk variable having a value between 0 and 1 based on a detected magnesium level in the patient;
(e) determining a risk variable having a value between 0 and 1 based on a detected presence of one or more diuretics in the patient;
(f) determining a risk variable having a value between 0 and 9 based on a detected presence of one or more antiarrhythmics in the patient:
(g) determining a risk variable having a value between 0 and 12 based on calculating a drug-specific index for the one or more medications in the patient's treatment regimen, including the patient's use of OT-prolonging drugs and/or a presence of drug-drug interactions, and
(f) determining a risk variable having a value between 0 and 10 based on the patient's QT interval;
the method further comprising combining the determined risk variables from the one or more of steps (a)-(g) to obtain a patient-specific score, wherein a patient-specific score exceeding a predetermined threshold value is indicative that the patient has an increased risk of long QT syndrome or Torsades de Pointes.
3. The ex vivo method of claim 1 , further comprising: treating a patient with the medication determined to have the drug-specific index indicative of an increased risk of long QT syndrome or Torsades de Pointes in combination with the at least one other drug, wherein the treatment of the patient comprises the steps of:
administering a pharmaceutical composition to the patient comprising a therapeutically effective amount of the medication or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
determining whether the patient has an increased risk of developing long QT syndrome or Torsades de Pointes due to a patient-specific score that is indicative of an increased risk of developing long QT syndrome or Torsades de Pointes; and
halting treatment of the patient with the pharmaceutical composition.
4. The ex vivo method of claim 3 , further comprising the step of administering an additional pharmaceutical composition to the patient that does not include the medication.
5. The ex vivo method of claim 1 , wherein the predetermined threshold value has a value of 15.
6. The ex vivo 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.
7. The ex vivo 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.
8. The ex vivo 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.
9. The ex vivo method of claim 2 , wherein the predetermined threshold value has a value of 10.