Compositions and Methods for Treating Anemia
Provided herein are specific doses of, and dosing regimens for, using a HIF prolyl hydroxylase inhibitor in treating or preventing anemia, such as anemia secondary to or associated with chronic kidney disease, anemia secondary to or associated with non-dialysis dependent chronic kidney disease anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.
1 - 56 . (canceled)
57 . A tablet formulation comprising an intra-granular component, an extra-granular component, and a film coating component,
wherein the intra-granular component comprises
about 60% to about 70% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid,
or a pharmaceutically acceptable salt thereof,
about 20% to about 30% by weight of microcrystalline cellulose,
about 2.5% to about 3.5% by weight of sodium starch glycolate, and
about 2.3% to about 3.3% by weight of a hydroxypropyl methylcellulose;
wherein the extra-granular component comprises
about 2.5% to about 3.5% by weight of a sodium starch glycolate,
about 0.2% to about 0.3% by weight of colloidal silicon dioxide, and
about 0.55% to about 0.95% by weight of magnesium stearate; and
wherein the film coating component comprises about 1.0% to about 8% by weight of a tablet coating, and
wherein the tablet formulation comprises about 75-600 mg of Compound 1.
58 . The tablet formulation of claim 57 ,
wherein the intra-granular component comprises
about 65% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid,
or a pharmaceutically acceptable salt thereof,
about 25% by weight of microcrystalline cellulose,
about 3.0% by weight of sodium starch glycolate, and
about 2.8% by weight of a hydroxypropyl methylcellulose;
wherein the extra-granular component comprises
about 3.0% by weight of a sodium starch glycolate,
about 0.25% by weight of colloidal silicon dioxide, and
about 0.75% by weight of magnesium stearate; and
wherein the film coating component comprises about 1.0% to about 8% by weight of a tablet coating;
wherein the weight is the total weight of all intra-granular and extra-granular components.
59 . The tablet formulation of claim 57 , comprising about 75 mg of Compound 1.
60 . A method for treating anemia comprising administering to a patient the tablet formulation according to claim 57 .
61 . The method of claim 60 , wherein the anemia is secondary to non-dialysis dependent chronic kidney disease.
62 . The method of claim 61 , wherein the patient is a dialysis patient.
63 . A method for treating anemia comprising administering to a patient the tablet formulation according to claim 59 .
64 . The method of claim 60 , wherein the anemia is secondary to non-dialysis dependent chronic kidney disease.
65 . A method for treating anemia secondary to non-dialysis dependent chronic kidney disease, comprising administering a sufficient number of successive doses of a tablet formulation according to claim 57 to a patient having anemia secondary to non-dialysis dependent chronic kidney disease,
wherein the patient has at least 2, 3, 4, 5 or all of (i) an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m 2 , wherein the subject is not on dialysis and not expected to start dialysis within 3 months of beginning of treatment, (ii) a hemoglobin level of less than 10.0 g/dL prior to commencement of treatment, (iii) a ferritin level equal to or above 100 ng/ml within 4 weeks of commencement of treatment, (iv) a transferrin saturation (TSAT) level equal to or above 20% within 4 weeks commencement of treatment, (v) a folate measurement equal to or above the lower limit of normal within 4 weeks commencement of treatment, (vi) a vitamin B12 measurement equal to or above the lower limit of normal within 4 weeks commencement of treatment, and (vii) an age of at least 18 years; or
wherein the patient has at least 2, 3, 4, 5 or all of (i) an estimated glomerular filtration rate (eGFR) of less than 65 mL/min/1.73 m 2 , wherein the subject is not on dialysis and not expected to start dialysis within 3 months of beginning of treatment, (ii) a hemoglobin level of less than 10.0 g/dL prior to commencement of treatment, (iii) a ferritin level equal to or above 50 ng/ml within 4 weeks of commencement of treatment, (iv) a transferrin saturation (TSAT) level equal to or above 15% within 4 weeks commencement of treatment, (v) a folate measurement equal to or above the lower limit of normal within 4 weeks commencement of treatment, (vi) a vitamin B12 measurement equal to or above the lower limit of normal within 4 weeks commencement of treatment, and (vii) an age of at least 18 years.
66 . A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease comprising:
administering to the patient an initial daily dose of Compound 1 as a tablet formulation according to claim 57 ,
wherein:
if the Hgb has not increased by more than 0.5 g/dL above the baseline value after 4 weeks of daily administration at the initial daily dose of Compound 1, increasing the daily dose by 150 mg/day of Compound 1, and increasing the daily dose by 150 mg/day every 4 weeks until Hgb is above 10.0 g/dL;
if the Hgb rises rapidly during treatment, reducing the daily dose by 150 mg/day;
if the Hgb falls below 10.0 g/dL, increasing the daily dose by 150 mg/day;
if the Hgb level exceeds 11.0 g/dL, interrupting treatment until the Hgb decreases to 10.5 g/dL or less, and thereafter resuming daily dosing with a daily dose reduced by 150 mg/day; and
if a dose adjustment is required to maintain Hgb at the desired level, adjusting the daily dose by 150 mg/day;
or wherein:
if the Hgb has not increased by more than 0.5 g/dL above the baseline value after 4 weeks of daily administration at the initial daily dose of Compound 1, increasing the daily dose by 150 mg/day of Compound 1, and increasing the daily dose by 150 mg/day every 4 weeks until Hgb is above 10.0 g/dL;
if the Hgb rises rapidly during treatment, reducing the daily dose by 150 mg/day;
if the Hgb falls below 10.0 g/dL, increasing the daily dose by 150 mg/day;
if the Hgb level exceeds 12.0 g/dL, reducing the daily dose by 150 mg/day, and if Hgb level exceeds 13.0 g/dL, interrupting treatment until the Hgb decreases to 12.5 g/dL or less, and thereafter resuming daily dosing with a daily dose reduced by 150 mg/day; and
if a dose adjustment is required to maintain Hgb at the desired level, adjusting the daily dose by 150 mg/day;
or wherein:
if a dose adjustment is required to maintain Hgb at the desired level, adjusting the daily dose by 150 mg/day;
if the Hgb rises rapidly during treatment, reducing the daily dose by 150 mg/day;
if the Hgb falls below 10.0 g/dL, increasing the daily dose by 150 mg/day; and
if the Hgb level exceeds 11.0 g/dL, interrupting treatment until the Hgb decreases to 10.5 g/dL or less, and thereafter resuming dosing with a daily dose reduced by 150 mg/day.
67 . A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease comprising:
administering to the patient an initial daily dose of Compound 1 as a tablet formulation according to claim 57 ; and
wherein:
if the Hgb has not increased by more than 0.5 g/dL above the baseline value after 4 weeks of daily administration at the initial daily dose of Compound 1, increasing the daily dose by 150 mg/day of Compound 1, and increasing the daily dose by 150 mg/day every 4 weeks until Hgb is above 10.0 g/dL;
if the Hgb rises rapidly during treatment, reducing the daily dose by 150 mg/day;
if the Hgb falls below 10.0 g/dL, increasing the daily dose by 150 mg/day;
if the Hgb level exceeds 12.0 g/dL, reducing the daily dose by 150 mg/day, and if Hgb level exceeds 13.0 g/dL, interrupting treatment until the Hgb decreases to 12.5 g/dL or less, and thereafter resuming daily dosing with a daily dose reduced by 150 mg/day; and
if a dose adjustment is required to maintain Hgb at the desired level, adjusting the daily dose by 150 mg/day.
68 . The method of claim 67 , wherein the baseline value is determined immediately prior to the first administration of Compound 1.
69 . The method of claim 67 , wherein the Hgb rises rapidly if the Hgb rises more than 1.0 g/dL in any 2-week period.
70 . The method of claim 67 , wherein the daily dose is administered once daily.
71 . The method of claim 67 , wherein the daily dose is administered at the same time of day.
72 . The method of claim 71 , wherein the initial daily dose is administered in the morning.
73 . The method of claim 72 , wherein the initial daily dose is administered between 7 am and 2 pm.
74 . A method of claim for treating anemia secondary to non-dialysis dependent chronic kidney disease, comprising administering a tablet formulation comprising an intra-granular component, an extra-granular component, and a film coating component, wherein the intra-granular component of the tablet formulation comprises:
about 150 mg of Compound 1,
about 57.46 mg microcrystalline cellulose,
about 6.90 mg sodium starch glycolate, and
about 6.44 mg hydroxypropyl methylcellulose; and
wherein the total weight of the intra-granular and extra-granular components is about 230 mg.
75 . The method of claim 74 , wherein the extra-granular component of the tablet formulation comprises:
about 6.9 mg sodium starch glycolate,
about 0.575 mg colloidal silicon dioxide; and
about 1.725 mg magnesium stearate.
76 . The method of claim 75 , wherein the tablet formulation is administered to the patient once daily.