Identification

Summary

Mitapivat is a pyruvate kinase activator used to treat hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

Brand Names
Pyrukynd 5 Mg 4-week
Generic Name
Mitapivat
DrugBank Accession Number
DB16236
Background

Mitapivat is a novel, first-in-class pyruvate kinase activator. It works to increase the activity of erythrocyte pyruvate kinase, a key enzyme involved in the survival of red blood cells. Defects in the pyruvate kinase enzyme in various red blood cells disorders lead to the lack of energy production for red blood cells, leading to lifelong premature destruction of red blood cells or chronic hemolytic anemia.1

On February 17, 2022, the FDA approved mitapivat as the first disease-modifying treatment for hemolytic anemia in adults with pyruvate kinase (PK) deficiency, a rare, inherited disorder leading to lifelong hemolytic anemia.6 Mitapivat has also been investigated in other hereditary red blood cell disorders associated with hemolytic anemia, such as sickle cell disease and alpha- and beta-thalassemia.1

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 450.56
Monoisotopic: 450.172561887
Chemical Formula
C24H26N4O3S
Synonyms
  • Mitapivat
  • Pkr-in-1
External IDs
  • AG-348

Pharmacology

Indication

Mitapivat is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.5

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Mitapivat is a pyruvate kinase activator that works to increase the activity of erythrocyte pyruvate kinase, an enzyme responsible for energy production for and survival of red blood cells. It is effective in upregulating the activity of both wild-type and mutant forms of erythrocyte pyruvate kinase.1,5

Interestingly, mitapivat is a mild-to-moderate inhibitor of the aromatase enzyme (CYP19A1),1 which is an enzyme involved in biosynthesis of estrogens from androgen precursors. Inhibition of aromatase is associated with bone density loss, as estrogen mediates suppressive, antiresorptive effects on osteoclasts and generally favours bone formation over resorption. Thus, low estrogen levels can increase bone turnover and osteoclast activity, resulting in net bone loss and decreased bone quality.2 Inhibition of aromatase by mitapivat may have some clinical implications, as patients with pyruvate kinase deficiency have considerably high rate of osteopenia and osteoporosis. The long-term effect of mitapivant on bond mineral density requires further investigation. One study suggests that this off-target effect may have negligible clinical effects on adults, but may potentially have some clinical implications in developing children.1

Mechanism of action

The pyruvate kinase enzyme is an ATP-generating enzyme involved in the Embden–Meyerhof glycolytic pathway: it catalyzes the conversion of phosphoenolpyruvate to pyruvate in the final step of glycolysis, generating adenosine triphosphate (ATP), which is critical for cellular maintenance and survival. One of the four isoforms of pyruvate kinase - erythrocyte pyruvate kinase or PKR - is dedicated to red blood cells (RBCs). Compared to most human cells, RBCs lack the metabolic machinery required for aerobic metabolism of glucose and generation of ATP; thus, they rely on anaerobic glycolysis for ATP production. The deficiency of ATP due to glycolytic enzyme defects leads to shortened lifespan and premature destruction of RBCs in the form of chronic hemolytic anemia and ineffective erythropoiesis.1 Pyruvate kinase deficiency is a rare hereditary disorder affecting RBC glycolysis, caused by mutations in PKLR, the gene encoding the RBC (PKR) and liver-specific isoforms (PKL) of pyruvate kinase. Pyruvate kinase deficiency is associated with a build-up of 2,3-disphosphoglycerate (2,3-DPG), an upstream metabolite in glycolysis, and deficient ATP levels.4

Erythrocyte pyruvate kinase is an allosterically regulated homotetrameric enzyme 4 that is normally activated by fructose bisphosphate (FBP) in an allosteric fashion. Mitapivat is also an allosteric pyruvate kinase activator but binds to a different allosteric site from FBP on the PKR tetramer. This allows for the activation of both wild-type and mutant forms of erythrocyte pyruvate kinase, including those not induced by FBP.1,5 Upon binding to pyruvate kinase, mitapivat stabilizes the active tetrameric form of the enzyme and enhances its affinity for its substrate, phosphoenolpyruvate.3 Mitapivat upregulates erythrocyte pyruvate kinase activity, increases ATP production, and reduces levels of 2,3-DPG.1,5

TargetActionsOrganism
APyruvate kinase PKLR
activator
Humans
UCytochrome P450 19A1
inhibitor
Humans
Absorption

The absolute bioavailability of mitapivat after a single dose is approximately 73%. Mitapivat exposure increases dose-proportionally. Following twice-daily oral administration of mitapivat at the dose of 5 mg, 20 mg, and 50 mg, the mean (CV%) Cmax at steady state were 101.2 (17%) ng/mL, 389.9 (18%) ng/mL, and 935.2 (18%) ng/mL, respectively. The mean (CV%) AUC were 450.4 (28%) ng x h/mL, 1623.8 (28%) ng x h/mL, and 3591.4 (28%) ng x h/mL, respectively. The median Tmax values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily.

In healthy subjects, a high-fat meal did not affect the drug exposure but reduced the rate of mitapivat absorption, with a 42% reduction in Cmax and a delay in Tmax of 2.3 hours when compared to dosing under fasted conditions.5

Volume of distribution

The mean volume of distribution at steady state (Vss) was 42.5 L. 5

Protein binding

Mitapivat is 97.7% bound to plasma proteins, with an RBC-to-plasma ratio of 0.37.5

Metabolism

According to in vitro studies, mitapivat is primarily metabolized by CYP3A4.5 It is also a substrate of CYP1A2, CYP2C8, and CYP2C9.1 Following a single oral dose administration of 120 mg of radiolabeled mitapivat in healthy subjects, unchanged mitapivat was the major circulating component in plasma.5

Route of elimination

Mitapivat is primary eliminated via hepatic metabolism.1 After a single oral administration of radiolabeled mitapivat in healthy subjects, the total recovery of administered radioactive dose was 89.2%. About 49.6% of radioactivity was recovered in the urine with 2.6% excreted as unchanged mitapivat. About 39.6% of radioactivity was recovered in the feces with less than 1% being the unchanged drug.5

Half-life

In patients with pyruvate kinase deficiency receiving multiple doses of 5 mg mitapivat twice daily to 20 mg twice daily, the mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours.5

Clearance

Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.5

Adverse Effects
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Toxicity

There is no information available regarding the LD50 and overdose profile of mitapivat.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirThe metabolism of Abacavir can be increased when combined with Mitapivat.
AbametapirThe serum concentration of Mitapivat can be increased when it is combined with Abametapir.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Mitapivat.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Mitapivat.
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Mitapivat.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Mitapivat.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Mitapivat.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Mitapivat.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Mitapivat.
AlbendazoleThe metabolism of Albendazole can be increased when combined with Mitapivat.
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Food Interactions
  • Take with or without food. Food has a negligible effect on the exposure of mitapivat, but may reduce the rate of drug absorption, Cmax, and Tmax.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Mitapivat sulfateN4JTA67V3ONot AvailableNot applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PyrukyndTablet, film coated50 mg/1OralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndTablet, film coated20 mg/1OralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndTablet, film coated5 mg/1OralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndTablet, film coated5 mg/1OralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
PyrukyndMitapivat (20 mg/1) + Mitapivat (50 mg/1)Kit; Tablet, film coatedOralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndMitapivat (5 mg/1) + Mitapivat (20 mg/1)Kit; Tablet, film coatedOralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndMitapivat (20 mg/1) + Mitapivat (50 mg/1)Kit; Tablet, film coatedOralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag
PyrukyndMitapivat (5 mg/1) + Mitapivat (20 mg/1)Kit; Tablet, film coatedOralAgios Pharmaceuticals, Inc.2022-02-18Not applicableUS flag

Categories

ATC Codes
G01AE10 — Combinations of sulfonamides
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
2WTV10SIKH
CAS number
1260075-17-9
InChI Key
XAYGBKHKBBXDAK-UHFFFAOYSA-N
InChI
InChI=1S/C24H26N4O3S/c29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22/h1-5,8-12,18,26H,6-7,13-17H2
IUPAC Name
N-{4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl}quinoline-8-sulfonamide
SMILES
O=C(N1CCN(CC2CC2)CC1)C1=CC=C(NS(=O)(=O)C2=CC=CC3=C2N=CC=C3)C=C1

References

General References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]
  2. Perez EA, Weilbaecher K: Aromatase inhibitors and bone loss. Oncology (Williston Park). 2006 Aug;20(9):1029-39; discussion 1039-40, 1042, 1048. [Article]
  3. Matte A, Federti E, Kung C, Kosinski PA, Narayanaswamy R, Russo R, Federico G, Carlomagno F, Desbats MA, Salviati L, Leboeuf C, Valenti MT, Turrini F, Janin A, Yu S, Beneduce E, Ronseaux S, Iatcenko I, Dang L, Ganz T, Jung CL, Iolascon A, Brugnara C, De Franceschi L: The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a beta-thalassemia mouse model. J Clin Invest. 2021 May 17;131(10). pii: 144206. doi: 10.1172/JCI144206. [Article]
  4. Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R: AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865. [Article]
  5. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
  6. GlobeNewsWire: Agios Announces FDA Approval of PYRUKYND® (mitapivat) as First Disease-Modifying Therapy for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency [Link]
ChemSpider
29763395
RxNav
2594468
ChEMBL
CHEMBL4299940
ZINC
ZINC000140430983
Wikipedia
Mitapivat

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentPyruvate Kinase Deficiency1
3CompletedTreatmentHemolytic Anemia / Pyruvate Kinase Deficiency2
3RecruitingTreatmentBeta Thalassemia Transfusion Dependent / Transfusion-dependent Alpha-Thalassemia1
3RecruitingTreatmentNon-Transfusion-dependent Alpha-Thalassemia / Non-Transfusion-dependent Beta-Thalassemia1
3RecruitingTreatmentPediatric Hemolytic Anemia / Pediatric Pyruvate Kinase Deficiency2
2Active Not RecruitingTreatmentPyruvate Kinase Deficiency1
2Active Not RecruitingTreatmentThalassaemic disorders1
2, 3RecruitingTreatmentSickle Cell Disease (SCD)1
1CompletedBasic ScienceHealthy Subjects (HS)1
1CompletedOtherHealthy Subjects (HS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Kit; tablet, film coatedOral
Tablet, film coatedOral20 mg/1
Tablet, film coatedOral5 mg/1
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9193701No2015-11-242032-10-26US flag
US9682080No2017-06-202032-05-03US flag
US9980961No2018-05-292032-05-03US flag
US10632114No2020-04-282032-05-03US flag
US11234976No2018-10-112038-10-11US flag
US11254652No2018-11-212038-11-21US flag
US8785450No2014-07-222031-02-24US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0329 mg/mLALOGPS
logP3.08ALOGPS
logP1.62ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)6.79ChemAxon
pKa (Strongest Basic)7.64ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area82.61 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity123.68 m3·mol-1ChemAxon
Polarizability46.21 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Pyruvate kinase activity
Specific Function
Plays a key role in glycolysis.
Gene Name
PKLR
Uniprot ID
P30613
Uniprot Name
Pyruvate kinase PKLR
Molecular Weight
61829.575 Da
References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]
  2. Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW, Van Beers EJ, Kung C, Van Wijk R: AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865. [Article]
  3. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]
  2. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]
  2. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Al-Samkari H, van Beers EJ: Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi: 10.1177/20406207211066070. eCollection 2021. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: PYRUKYND (mitapivat) tablets, for oral use [Link]

Drug created at December 15, 2020 18:16 / Updated at March 08, 2022 12:10