METHODS OF ADMINISTERING VOXELOTOR
Provided herein are methods of using voxelotor for the treatment of sickle cell disease in patients, wherein the patient is about 4 years old to less than about 12 years old. Provided herein are methods of using voxelotor for the treatment of sickle cell disease in patients also having severe hepatic impairment. Also provided herein are methods for administering voxelotor and avoiding or lessening adverse drug interactions with a CYP3A4 inducer or inhibitor. Also provided herein are methods for avoiding interactions with voxelotor, a moderate CYP3A4 inhibitor.
1 . A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 600 mg to 1500 mg of voxelotor per day, wherein the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
2 . The method of claim 1 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 1500 mg of voxelotor per day.
3 . The method of claim 1 , wherein the patient's body weight is about 20 kg to less than about 40 kg, and the patient is administered 900 mg of voxelotor per day.
4 . The method of claim 1 , wherein the patient's body weight is about 10 kg to less than about 20 kg, and the patient is administered 600 mg of voxelotor per day.
5 . A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 300 mg to 1000 mg of voxelotor per day, wherein the patient has severe hepatic impairment, the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
6 . The method of claim 5 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 900 mg of voxelotor per day.
7 . The method of claim 5 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 1000 mg of voxelotor per day.
8 . The method of claim 5 , wherein the patient's body weight is about 20 kg to less than about 40 kg, and the patient is administered 600 mg of voxelotor per day.
9 . The method of claim 5 , wherein the patient's body weight is about 10 kg to less than about 20 kg, and the patient is administered 300 mg of voxelotor per day.
10 . The method of any one of claims 1-9 , wherein voxelotor is administered with food.
11 . The method of any one of claims 1-9 , wherein voxelotor is administered without food.
12 . The method of any one of claims 5-11 , wherein the patient has a Child-Pugh score of 10-15 points (Child-Pugh C).
13 . The method of any one of claims 5-11 , wherein the patient suffers from a chronic liver disease.
14 . The method of any one of claims 5-11 , wherein the patient suffers from a condition selected from the group consisting of liver fibrosis, cirrhosis, hepatocellular carcinoma, hepatic inflammation, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), portal hypertension, hepatic encephalopathy, hepatitis, and any combination thereof.
15 . The method of any one of claims 5-14 , wherein voxelotor is administered to the patient once daily.
16 . The method of any one of claims 5-15 , wherein voxelotor is administered to the patient in an oral formulation.
17 . The method of claim 16 , wherein the oral formulation is tablet.
18 . The method of any one of claims 1-17 , wherein voxelotor is administered to the patient in a single oral dose of one tablet daily, two tablets daily, or three tablets daily.
19 . A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 600 mg to 1500 mg of voxelotor once daily, wherein the patient has mild or moderate hepatic impairment, the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
20 . A method of concurrently administering voxelotor and a strong CYP3A4 inducer comprising administering to a patient a therapeutically effective amount of a strong CYP3A4 inducer and 2000 ng voxelotor orally once daily, wherein the patient is 12 years of age or older.
21 . A method of concurrently administering voxelotor and a strong CYP3A4 inducer comprising administering to a patient a therapeutically effective amount of a strong CYP3A4 inducer and 900 mg to 2100 mg voxelotor orally once daily, wherein the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
22 . The method of claim 21 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2000 mg of voxelotor per day.
23 . The method of claim 21 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2100 mg of voxelotor per day.
24 . The method of claim 21 , wherein the patient's body weight is about 20 kg to less than about 40 kg, and the patient is administered 1200 mg of voxelotor per day.
25 . The method of claim 21 , wherein the patient's body weight is about 10 kg to less than about 20 kg, and the patient is administered 900 mg of voxelotor per day.
26 . A method of administering voxelotor to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of voxelotor, and advising the patient one or more of the following:
(a) advising the patient that a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor should be avoided or discontinued;
(b) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor can alter the therapeutic effect of voxelotor;
(c) advising the patient that co-administration of voxelotor and a moderate CYP3A4 inducer or strong CYP3A4 inducer can decrease voxelotor plasma concentrations and may lead to reduced efficacy;
(d) advising the patient that co-administration of voxelotor and a strong CYP3A4 inhibitor can increase voxelotor plasma concentrations and may lead to increased toxicity;
(e) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index can increase the systemic exposure of the sensitive CYP3A4 substrate with a narrow therapeutic index;
(f) advising the patient to replace a strong CYP3A4 inhibitor or fluconazole with an alternative drug;
(g) if co-administration of a strong CYP3A4 inhibitor or fluconazole is unavoidable, decreasing the dose of voxelotor to 1000 mg per day;
(h) if co-administration of a moderate CYP3A4 inducer or strong CYP3A4 inducer is unavoidable, increasing the dose of voxelotor to 2500 mg per day;
(i) if co-administration of a CYP3A4 inducer is unavoidable and the patient is about 12 years old or older, increasing the dose of voxelotor to 2000 mg per day;
(j) if co-administration of a CYP3A4 inducer is unavoidable and the patient is about 4 years old to less than about 12 years old, increasing the dose of voxelotor to 900 mg to 2100 mg voxelotor mg per day depending on the patient's body weight;
(k) if co-administration of a strong CYP3A4 inducer is unavoidable and the patient is about 12 years old or older, increasing the dose of voxelotor to 2500 mg per day;
(l) if co-administration of a moderate CYP3A4 inducer is unavoidable and the patient is about 12 years old or older, increasing the dose of voxelotor to 2000 mg per day;
(m) if co-administration of a strong CYP3A4 inducer is unavoidable and the patient is about 4 years old to less than about 12 years old, increasing the dose of voxelotor to 900 mg to 2500 mg voxelotor mg per day depending on the patient's body weight;
(n) if co-administration of a moderate CYP3A4 inducer is unavoidable and the patient is about 4 years old to less than about 12 years old, increasing the dose of voxelotor to 900 mg to 2100 mg voxelotor mg per day depending on the patient's body weight; or
(o) if co-administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is unavoidable, decreasing the dose of the sensitive CYP3A4 substrate with a narrow therapeutic index.
27 . The method of any one of claims 1-19 and 21-26 , wherein the patient may suffer from pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache.
28 . The method of any one of claims 1-19 and 21-26 , wherein the patient may suffer from vomiting.
29 . The method of any one of claims 1-19 and 21-28 , wherein voxelotor is administered as an oral suspension.
30 . The method of any one of the preceding claims , wherein a tablet of voxelotor is dispersed in a liquid before administration.
31 . The method of claim 17 , wherein one tablet of voxelotor is dispersed in 5 mL of liquid.
32 . The method of claim 17 , wherein two tablets of voxelotor are dispersed in 10 mL of liquid.
33 . The method of claim 17 , wherein three tablets of voxelotor are dispersed in 15 mL of liquid.
34 . The method of claim 17 , wherein four tablets of voxelotor are dispersed in 20 mL of liquid.
35 . The method of claim 17 , wherein four tablets of voxelotor are dispersed in 20 mL of liquid.
36 . The method of claim 17 , wherein five tablets of voxelotor are dispersed in 25 mL of liquid.
37 . The method of claim 17 , wherein seven tablets of voxelotor are dispersed in 35 mL of liquid.
38 . The method of claim 17 , wherein eight tablets of voxelotor are dispersed in 40 mL of liquid.
39 . A method of concurrently administering voxelotor and a moderate CYP3A4 inducer comprising administering to a patient a therapeutically effective amount of a moderate CYP3A4 inducer and 2000 mg voxelotor orally once daily, wherein the patient is 12 years of age or older.
40 . A method of concurrently administering voxelotor and a strong CYP3A4 inducer comprising administering to a patient a therapeutically effective amount of a strong CYP3A4 inducer and 900 mg to 2500 mg voxelotor orally once daily, wherein the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
41 . The method of claim 40 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2500 mg of voxelotor per day.
42 . The method of claim 40 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2400 mg of voxelotor per day.
43 . The method of claim 40 , wherein the patient's body weight is about 20 kg to less than about 40 kg, and the patient is administered 1500 mg of voxelotor per day.
44 . The method of claim 40 , wherein the patient's body weight is about 10 kg to less than about 20 kg, and the patient is administered 900 mg of voxelotor per day.
45 . A method of concurrently administering voxelotor and a moderate CYP3A4 inducer comprising administering to a patient a therapeutically effective amount of a moderate CYP3A4 inducer and 900 mg to 2100 mg voxelotor orally once daily, wherein the patient is about 4 years old to less than about 12 years old, and the amount of voxelotor is determined by the patient's body weight.
46 . The method of claim 45 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2000 mg of voxelotor per day.
47 . The method of claim 45 , wherein the patient's body weight is about 40 kg or greater, and the patient is administered 2100 mg of voxelotor per day.
48 . The method of claim 45 , wherein the patient's body weight is about 20 kg to less than about 40 kg, and the patient is administered 1200 mg of voxelotor per day.
49 . The method of claim 45 , wherein the patient's body weight is about 10 kg to less than about 20 kg, and the patient is administered 900 mg of voxelotor per day.
50 . The method of any one of the preceding claims , further comprising administering to the patient hydroxyurea.