PRECLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS OF AG-519, AN ALLOSTERIC PYRUVATE KINASE-R ACTIVATOR
(Abstract release date: 05/19/16)
EHA Library. Yang H. 06/12/16; 135324; S830
Dr. Hua Yang
Contributions
Contributions
Abstract
Abstract: S830
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Room H5
Background
Pyruvate kinase (PK) deficiency is a rare genetic disease causing chronic hemolytic anemia. Symptoms vary in severity and include splenomegaly, iron overload and jaundice, and current treatments are supportive only. PK deficiency is caused by mutations in the red blood cell (RBC) isoform of PK (PK-R), a key enzyme in RBC glycolysis. Functional PK-R deficiency leads to increases in the upstream metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreases in the product adenosine triphosphate (ATP) in blood. Small molecule activation of mutant PK-R could restore the glycolytic pathway, and decrease hemolysis, leading to patient benefit. AG-519 is an orally available allosteric activator of both mutant and wild type PK-R currently in clinical development.
Aims
To explore the pharmacokinetic/pharmacodynamic (PK/PD) relationships of AG-519 with PK-R activity, ATP and 2,3-DPG in wild type PK-R mice, and to use data from animal studies to project the pharmacokinetic profile and efficacious dose of AG-519 in humans.
Methods
In vitro intrinsic clearance (CLint) was calculated in microsomes and hepatocytes from all species tested. In vivo PK/PD was analyzed in PK-R wild type C57/BL6 female mice. AG-519 or vehicle was given orally as a single dose, or for 5 and 13 twice-daily (BID) doses, at 1, 10, 50 and 150 mg/kg. Blood or plasma concentrations of AG-519, ATP and 2,3-DPG were measured at 0, 3, 6, 12, 24, 36, 48 and 72 h following the last dose by liquid chromatography with tandem mass spectrometry, with PK-R activity measured by colorimetric assessment of the reaction rate in blood cell lysates. For in vivo pharmacokinetic profiling of AG-519 in Sprague Dawley rats, Beagle dogs and cynomolgus monkeys, clearance (CL), volume of distribution at a steady state (Vss), terminal half-life (t½), and oral bioavailability (F) were calculated. The human profile was predicted by allometric scaling with correction factors.
Results
AG-519 showed moderate CL (1.13–2.51 L/h/kg), moderate Vss (2.08–6.44 L/kg), moderate to long t½ (6.3–9.8 h), rapid absorption (Tmax ≤1.2 h) and moderate oral bioavailability (6.9–19.5% with suspension formulation) in mouse, rat, dog and monkey. There was good in vitro to in vivo correlation in the CL estimates across species. In mouse PK/PD studies, dose-dependent increases in blood ATP levels were observed after 5 and 13 BID doses, but not after a single dose. In addition, dose-dependent decreases in 2,3-DPG were observed following both single and multiple doses of AG-519. There were dose-dependent increases in blood PK-R activity after single and multiple AG-519 doses. The AG-519 exposure to biomarker response (2,3-DPG, ATP and PK-R activity) relationship was described by an Emax model. With the projections of an effective t½ (4.1–7.1 h), CL (0.414 L/h/kg), Vss (2.95 L/kg), and F (22.5%) in humans, twice-daily dosing of 111 mg (range 62–134 mg) of AG-519 in humans is anticipated to achieve the EAUC90(0-12h) (the exposure required to achieve 90% of maximal effect on all three biomarkers) of 421 h•ng/mL.
Conclusion
AG-519 showed a favorable pharmacokinetic profile in several animal species, allowing prediction of its profile in humans. This, along with the clear PK/PD relationship established in the mouse model demonstrating activation of PK-R, allowed prediction of the AG-519 efficacious dose in humans. These data supported the decision to bring AG-519 into a phase 1 healthy volunteer study (NCT02630927).
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Hemolytic anemia, Pharmacokinetic
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Room H5
Background
Pyruvate kinase (PK) deficiency is a rare genetic disease causing chronic hemolytic anemia. Symptoms vary in severity and include splenomegaly, iron overload and jaundice, and current treatments are supportive only. PK deficiency is caused by mutations in the red blood cell (RBC) isoform of PK (PK-R), a key enzyme in RBC glycolysis. Functional PK-R deficiency leads to increases in the upstream metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreases in the product adenosine triphosphate (ATP) in blood. Small molecule activation of mutant PK-R could restore the glycolytic pathway, and decrease hemolysis, leading to patient benefit. AG-519 is an orally available allosteric activator of both mutant and wild type PK-R currently in clinical development.
Aims
To explore the pharmacokinetic/pharmacodynamic (PK/PD) relationships of AG-519 with PK-R activity, ATP and 2,3-DPG in wild type PK-R mice, and to use data from animal studies to project the pharmacokinetic profile and efficacious dose of AG-519 in humans.
Methods
In vitro intrinsic clearance (CLint) was calculated in microsomes and hepatocytes from all species tested. In vivo PK/PD was analyzed in PK-R wild type C57/BL6 female mice. AG-519 or vehicle was given orally as a single dose, or for 5 and 13 twice-daily (BID) doses, at 1, 10, 50 and 150 mg/kg. Blood or plasma concentrations of AG-519, ATP and 2,3-DPG were measured at 0, 3, 6, 12, 24, 36, 48 and 72 h following the last dose by liquid chromatography with tandem mass spectrometry, with PK-R activity measured by colorimetric assessment of the reaction rate in blood cell lysates. For in vivo pharmacokinetic profiling of AG-519 in Sprague Dawley rats, Beagle dogs and cynomolgus monkeys, clearance (CL), volume of distribution at a steady state (Vss), terminal half-life (t½), and oral bioavailability (F) were calculated. The human profile was predicted by allometric scaling with correction factors.
Results
AG-519 showed moderate CL (1.13–2.51 L/h/kg), moderate Vss (2.08–6.44 L/kg), moderate to long t½ (6.3–9.8 h), rapid absorption (Tmax ≤1.2 h) and moderate oral bioavailability (6.9–19.5% with suspension formulation) in mouse, rat, dog and monkey. There was good in vitro to in vivo correlation in the CL estimates across species. In mouse PK/PD studies, dose-dependent increases in blood ATP levels were observed after 5 and 13 BID doses, but not after a single dose. In addition, dose-dependent decreases in 2,3-DPG were observed following both single and multiple doses of AG-519. There were dose-dependent increases in blood PK-R activity after single and multiple AG-519 doses. The AG-519 exposure to biomarker response (2,3-DPG, ATP and PK-R activity) relationship was described by an Emax model. With the projections of an effective t½ (4.1–7.1 h), CL (0.414 L/h/kg), Vss (2.95 L/kg), and F (22.5%) in humans, twice-daily dosing of 111 mg (range 62–134 mg) of AG-519 in humans is anticipated to achieve the EAUC90(0-12h) (the exposure required to achieve 90% of maximal effect on all three biomarkers) of 421 h•ng/mL.
Conclusion
AG-519 showed a favorable pharmacokinetic profile in several animal species, allowing prediction of its profile in humans. This, along with the clear PK/PD relationship established in the mouse model demonstrating activation of PK-R, allowed prediction of the AG-519 efficacious dose in humans. These data supported the decision to bring AG-519 into a phase 1 healthy volunteer study (NCT02630927).
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Hemolytic anemia, Pharmacokinetic
Abstract: S830
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Room H5
Background
Pyruvate kinase (PK) deficiency is a rare genetic disease causing chronic hemolytic anemia. Symptoms vary in severity and include splenomegaly, iron overload and jaundice, and current treatments are supportive only. PK deficiency is caused by mutations in the red blood cell (RBC) isoform of PK (PK-R), a key enzyme in RBC glycolysis. Functional PK-R deficiency leads to increases in the upstream metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreases in the product adenosine triphosphate (ATP) in blood. Small molecule activation of mutant PK-R could restore the glycolytic pathway, and decrease hemolysis, leading to patient benefit. AG-519 is an orally available allosteric activator of both mutant and wild type PK-R currently in clinical development.
Aims
To explore the pharmacokinetic/pharmacodynamic (PK/PD) relationships of AG-519 with PK-R activity, ATP and 2,3-DPG in wild type PK-R mice, and to use data from animal studies to project the pharmacokinetic profile and efficacious dose of AG-519 in humans.
Methods
In vitro intrinsic clearance (CLint) was calculated in microsomes and hepatocytes from all species tested. In vivo PK/PD was analyzed in PK-R wild type C57/BL6 female mice. AG-519 or vehicle was given orally as a single dose, or for 5 and 13 twice-daily (BID) doses, at 1, 10, 50 and 150 mg/kg. Blood or plasma concentrations of AG-519, ATP and 2,3-DPG were measured at 0, 3, 6, 12, 24, 36, 48 and 72 h following the last dose by liquid chromatography with tandem mass spectrometry, with PK-R activity measured by colorimetric assessment of the reaction rate in blood cell lysates. For in vivo pharmacokinetic profiling of AG-519 in Sprague Dawley rats, Beagle dogs and cynomolgus monkeys, clearance (CL), volume of distribution at a steady state (Vss), terminal half-life (t½), and oral bioavailability (F) were calculated. The human profile was predicted by allometric scaling with correction factors.
Results
AG-519 showed moderate CL (1.13–2.51 L/h/kg), moderate Vss (2.08–6.44 L/kg), moderate to long t½ (6.3–9.8 h), rapid absorption (Tmax ≤1.2 h) and moderate oral bioavailability (6.9–19.5% with suspension formulation) in mouse, rat, dog and monkey. There was good in vitro to in vivo correlation in the CL estimates across species. In mouse PK/PD studies, dose-dependent increases in blood ATP levels were observed after 5 and 13 BID doses, but not after a single dose. In addition, dose-dependent decreases in 2,3-DPG were observed following both single and multiple doses of AG-519. There were dose-dependent increases in blood PK-R activity after single and multiple AG-519 doses. The AG-519 exposure to biomarker response (2,3-DPG, ATP and PK-R activity) relationship was described by an Emax model. With the projections of an effective t½ (4.1–7.1 h), CL (0.414 L/h/kg), Vss (2.95 L/kg), and F (22.5%) in humans, twice-daily dosing of 111 mg (range 62–134 mg) of AG-519 in humans is anticipated to achieve the EAUC90(0-12h) (the exposure required to achieve 90% of maximal effect on all three biomarkers) of 421 h•ng/mL.
Conclusion
AG-519 showed a favorable pharmacokinetic profile in several animal species, allowing prediction of its profile in humans. This, along with the clear PK/PD relationship established in the mouse model demonstrating activation of PK-R, allowed prediction of the AG-519 efficacious dose in humans. These data supported the decision to bring AG-519 into a phase 1 healthy volunteer study (NCT02630927).
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Hemolytic anemia, Pharmacokinetic
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:30 - 08:45
Location: Room H5
Background
Pyruvate kinase (PK) deficiency is a rare genetic disease causing chronic hemolytic anemia. Symptoms vary in severity and include splenomegaly, iron overload and jaundice, and current treatments are supportive only. PK deficiency is caused by mutations in the red blood cell (RBC) isoform of PK (PK-R), a key enzyme in RBC glycolysis. Functional PK-R deficiency leads to increases in the upstream metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreases in the product adenosine triphosphate (ATP) in blood. Small molecule activation of mutant PK-R could restore the glycolytic pathway, and decrease hemolysis, leading to patient benefit. AG-519 is an orally available allosteric activator of both mutant and wild type PK-R currently in clinical development.
Aims
To explore the pharmacokinetic/pharmacodynamic (PK/PD) relationships of AG-519 with PK-R activity, ATP and 2,3-DPG in wild type PK-R mice, and to use data from animal studies to project the pharmacokinetic profile and efficacious dose of AG-519 in humans.
Methods
In vitro intrinsic clearance (CLint) was calculated in microsomes and hepatocytes from all species tested. In vivo PK/PD was analyzed in PK-R wild type C57/BL6 female mice. AG-519 or vehicle was given orally as a single dose, or for 5 and 13 twice-daily (BID) doses, at 1, 10, 50 and 150 mg/kg. Blood or plasma concentrations of AG-519, ATP and 2,3-DPG were measured at 0, 3, 6, 12, 24, 36, 48 and 72 h following the last dose by liquid chromatography with tandem mass spectrometry, with PK-R activity measured by colorimetric assessment of the reaction rate in blood cell lysates. For in vivo pharmacokinetic profiling of AG-519 in Sprague Dawley rats, Beagle dogs and cynomolgus monkeys, clearance (CL), volume of distribution at a steady state (Vss), terminal half-life (t½), and oral bioavailability (F) were calculated. The human profile was predicted by allometric scaling with correction factors.
Results
AG-519 showed moderate CL (1.13–2.51 L/h/kg), moderate Vss (2.08–6.44 L/kg), moderate to long t½ (6.3–9.8 h), rapid absorption (Tmax ≤1.2 h) and moderate oral bioavailability (6.9–19.5% with suspension formulation) in mouse, rat, dog and monkey. There was good in vitro to in vivo correlation in the CL estimates across species. In mouse PK/PD studies, dose-dependent increases in blood ATP levels were observed after 5 and 13 BID doses, but not after a single dose. In addition, dose-dependent decreases in 2,3-DPG were observed following both single and multiple doses of AG-519. There were dose-dependent increases in blood PK-R activity after single and multiple AG-519 doses. The AG-519 exposure to biomarker response (2,3-DPG, ATP and PK-R activity) relationship was described by an Emax model. With the projections of an effective t½ (4.1–7.1 h), CL (0.414 L/h/kg), Vss (2.95 L/kg), and F (22.5%) in humans, twice-daily dosing of 111 mg (range 62–134 mg) of AG-519 in humans is anticipated to achieve the EAUC90(0-12h) (the exposure required to achieve 90% of maximal effect on all three biomarkers) of 421 h•ng/mL.
Conclusion
AG-519 showed a favorable pharmacokinetic profile in several animal species, allowing prediction of its profile in humans. This, along with the clear PK/PD relationship established in the mouse model demonstrating activation of PK-R, allowed prediction of the AG-519 efficacious dose in humans. These data supported the decision to bring AG-519 into a phase 1 healthy volunteer study (NCT02630927).
Session topic: Non-malignant hematopoietic disorders
Keyword(s): Hemolytic anemia, Pharmacokinetic
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