MITAPIVAT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H26N4O3S
Molecular Weight	450.553
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O=C(N1CCN(CC2CC2)CC1)C3=CC=C(NS(=O)(=O)C4=CC=CC5=CC=CN=C45)C=C3

InChI

InChIKey=XAYGBKHKBBXDAK-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216196s000lbl.pdf|

Mitapivat (AG-348; PKM2 activator 1020) is a novel, first-in-class oral small molecule allosteric activator of the pyruvate kinase enzyme. Mitapivat has been shown to significantly upregulate both wild-type and numerous mutant forms of erythrocyte pyruvate kinase (PKR), increasing adenosine triphosphate (ATP) production and reducing levels of 2,3-diphosphoglycerate. Given this mechanism, mitapivat has been evaluated in clinical trials in a wide range of hereditary hemolytic anemias, including pyruvate kinase deficiency (PKD), sickle cell disease, and the thalassemias. Mitapivat was approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States in February 2022, and in the European Union in November 2022.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Pyruvate kinase PKLR 3 Target ID: P30613 Gene ID: 5313.0 Gene Symbol: PKLR Target Organism: Homo sapiens (Human) Sources: https://www.google.com/patents/WO2011002817A1	Positive Allosteric Modulator 186
Pyruvate kinase isozymes M1/M2 12 Target ID: CHEMBL1075189 Sources: https://www.google.com/patents/WO2011002817A1\|https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216196s000lbl.pdf	Activator 1447

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hemolytic anemia due to pyruvate kinase deficiency 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216196s000lbl.pdf	Primary		Approved 8583	PYRUKYND Approved Use Indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency Launch Date 2022

C_max

Value	Dose	Analyte	Population
101.2 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	5 mg 2 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
389.9 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	20 mg 2 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
935.2 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	50 mg 2 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
76 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1005 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
4425 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
248 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
255 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1287 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1322 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
2806 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
2094 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1033 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
938 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
131 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	5 mg 2 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
499 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	20 mg 2 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1178 ng/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	50 mg 2 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
450.4 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	5 mg 2 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
1623.8 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	20 mg 2 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3591.4 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	50 mg 2 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
304 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
4007 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
15642 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
778 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
938 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	15 mg 2 times / day multiple, oral dose: 15 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3279 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3358 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	60 mg 2 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
10034 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
8461 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	120 mg 1 times / day multiple, oral dose: 120 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3162 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
2628 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=215	50 mg 2 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
440 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	5 mg 2 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1582 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	20 mg 2 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3482 ng × h/mL OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=198	50 mg 2 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
5 h OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	5 mg 2 times / day steady-state, oral dose: 5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
5 h OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	20 mg 2 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
5 h OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=35 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=37	50 mg 2 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	MITAPIVAT plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
2.3% OTHER GOV'T https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=165 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf#page=141			MITAPIVAT plasma	Homo sapiens

Doses

Dose	Population	Adverse events
2500 mg single, oral Highest studied dose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	healthy, ADULT Health Status: healthy Age Group: ADULT Sex: unknown Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Disc. AE: insomnia, headache... AEs leading to discontinuation/dose reduction: insomnia (19%) headache (19%) insomnia (15%) headache (15%) insomnia (15%) headache (15%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
20 mg 2 times / day multiple, oral Studied dose Dose: 20 mg, 2 times / day Route: oral Route: multiple Dose: 20 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Disc. AE: Joint swelling, Back pain... AEs leading to discontinuation/dose reduction: Joint swelling (severe, 1 patient) Back pain (severe, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf

AEs

AE	Significance	Dose	Population
headache	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
headache	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
insomnia	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
insomnia	15% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
headache	19% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
insomnia	19% Disc. AE	50 mg 2 times / day steady, oral Recommended\|Studied dose Dose: 50 mg, 2 times / day Route: oral Route: steady Dose: 50 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
Back pain	severe, 1 patient Disc. AE	20 mg 2 times / day multiple, oral Studied dose Dose: 20 mg, 2 times / day Route: oral Route: multiple Dose: 20 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf
Joint swelling	severe, 1 patient Disc. AE	20 mg 2 times / day multiple, oral Studied dose Dose: 20 mg, 2 times / day Route: oral Route: multiple Dose: 20 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf	Sex: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 substrate 1946	inducer 440	substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT3 747 BSEP 550 OATP1B3 961 P-gp 1741 BCRP 910 OCT2 779 MATE1 415	CYP1A2 1197 OATP1B3 435 OATP1B1 503 BCRP 697 CYP3A5 446 P-gp 2052 UGT1A1 479	CYP2B6 669 CYP3A5 92 CYP2C8 198 UGT1A1 78 CYP2C19 329

Drug as perpetrator

Target	Modality	Activity
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	yes [IC50 12.1 uM]
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes [IC50 12.8 uM]
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	yes [IC50 22 uM]
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	yes [IC50 7.17 uM]
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 144.0	yes [IC50 7.17 uM]
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
CYP2C8 1117	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
CYP3A5 201	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes
UGT1A1 303	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 38 \| 119	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 142.0	minor
CYP2D6 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 142.0	minor
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 36.0	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 36.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 36.0	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26 \| 36	yes
UGT1A1 479	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26.0	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26 \| 37 \| 118 \| 185	yes	yes (co-administration study) Comment: Itraconazole increased the AUC∞ and Cmax of mitapivat by 4.9- and 1.7-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26 \| 37 \| 118 \| 185
CYP3A5 446	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26 \| 37 \| 118 \| 185	yes	yes (co-administration study) Comment: Itraconazole increased the AUC∞ and Cmax of mitapivat by 4.9- and 1.7-fold Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 26 \| 37 \| 118 \| 185

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216196Orig1s000IntegratedR.pdf Page: 139.0

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks

Route of Administration: Oral

In Vitro Use Guide

In human red blood cells, mitapivat activates PKR with AC50 and AC90 for PKR activation of 0.0619±0.0346 uM and 1.002±1.109 uM, respectively. The average maximum percent PKR activation was 274%±56%. It was demonstrated that while the WT PKR was activated by mitapivat with AC50 0.013 uM the 10 mutant PKR isoforms evaluated were activated with AC50 values ranged approximately 0.009 to 0.059 uM.

Name

Type

Language

MITAPIVAT

Official Name

English

mitapivat [INN]

Preferred Name

English

8-QUINOLINESULFONAMIDE, N-(4-((4-(CYCLOPROPYLMETHYL)-1-PIPERAZINYL)CARBONYL)PHENYL)-

Systematic Name

English

N-(4-((4-(CYCLOPROPYLMETHYL)-1-PIPERAZINYL)CARBONYL)PHENYL)-8-QUINOLINESULFONAMIDE

Systematic Name

English

PKR-IN-1

Common Name

English

Mitapivat [WHO-DD]

Common Name

English

AG-348

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

739920