PIRTOBRUTINIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H21F4N5O3
Molecular Weight	479.4275
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC=C(F)C=C1C(=O)NCC2=CC=C(C=C2)C3=NN([C@@H](C)C(F)(F)F)C(N)=C3C(N)=O

InChI

InChIKey=FWZAWAUZXYCBKZ-NSHDSACASA-N

InChI=1S/C22H21F4N5O3/c1-11(22(24,25)26)31-19(27)17(20(28)32)18(30-31)13-5-3-12(4-6-13)10-29-21(33)15-9-14(23)7-8-16(15)34-2/h3-9,11H,10,27H2,1-2H3,(H2,28,32)(H,29,33)/t11-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C22H21F4N5O3
Molecular Weight	479.4275
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma|https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf

Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models. On January 27, 2023, the Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase BTK 24 Target ID: CHEMBL5251 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	Inhibitor 8504		5.69 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Mantle cell lymphoma 24 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	Primary		Approved 8583	JAYPIRCA Approved Use JAYPIRCA is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor Launch Date 2023

C_max

Value	Dose	Co-administered	Analyte	Population
6460 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
3670 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
91300 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
81800 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
19 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
19 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
4% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg 1 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN
4% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		PIRTOBRUTINIB plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
900 mg single, oral Highest studied dose Dose: 900 mg Route: oral Route: single Dose: 900 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#page=68	healthy, ADULT Health Status: healthy Age Group: ADULT Sex: unknown Food Status: UNKNOWN Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#page=68	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#page=68
200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	Disc. AE: Pneumonia, Neutropenia... AEs leading to discontinuation/dose reduction: Pneumonia (>5) Neutropenia (>5) Pneumonia (>1) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf

AEs

AE	Significance	Dose	Population
Pneumonia	>1 Disc. AE	200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf
Neutropenia	>5 Disc. AE	200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf
Pneumonia	>5 Disc. AE	200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252 inducer 1087	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT3 747 OCT1 620 CYP2B6 926 MATE2-K 77 P-gp 1741 CYP2C8 1057 OATP1B1 1079 BCRP 910 MATE1 415 OCT2 779 OATP1B3 961 OAT1 725	UGT1A8 323 OCT1 393 OATP1B1 503 UGT1A9 423 OATP1B3 435 BSEP 63 BCRP 697 P-gp 2052	CYP2C19 329 CYP3A5 92 CYP2B6 669

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	minor [IC50 >60 uM]
MATE2-K 77	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OCT1 656	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	no	no (co-administration study) Comment: In patients with cancer, there was no clinically meaningful effect of pirtobrutinib on serum creatinine. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0	yes [Ki <=25.2 uM]	no (co-administration study) Comment: Pirtobrutinib (200mg, QD) increased S-warfarin (10mg, SD) AUCinf by 11% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70.0
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 76	yes [Ki <=25.2 uM]	weak (co-administration study) Comment: Pirtobrutinib (200mg, QD) increased midazolame (500 mug, SD) AUCinf by 70% and Cmax by 58% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 76
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78	yes [Ki <=25.2 uM]	yes (co-administration study) Comment: Pirtobrutinib increased repaglinide AUC by 130% and Cmax by 98% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	yes
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	yes
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	yes
CYP3A5 201	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	yes
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78	yes	weak (co-administration study) Comment: Pirtobrutinib increased digoxin AUCtau by 35% and Cmax by 55% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78	yes	yes (co-administration study) Comment: Pirtobrutinib (multi-dose) increased rosuvastatin AUCinf by 140% and Cmax by 146% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 70 \| 78

Drug as victim

Target	Modality	Activity	Clinical evidence
BSEP 63	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	no
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	no
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	no
OCT1 393	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf Page: 10.0	no
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#pae=69 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf#page=10 Page: 69 \| 10	yes
UGT1A8 323	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 69.0	yes
UGT1A9 423	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 69.0	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#page=69 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf#page=10 Page: 69 \| 10	yes	no (co-administration study) Comment: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with itraconazole (P-gp inhibitor). Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf#page=69 \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059Orig1s000Corrected_lbl.pdf#page=10 Page: 69 \| 10
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 69 \| 70 \| 76	yes	weak (co-administration study) Comment: Itraconazole increased pirtobrutinib AUCinf by 49% and Cmax by 4% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 69 \| 70 \| 76

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216059Orig1s000MultidisciplineR.pdf Page: 39.0

PubMed

Title	Date	PubMed
New Treatment Options for Newly-Diagnosed and Relapsed Chronic Lymphocytic Leukemia.	2022-06	35357653
Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia.	2022-05-20	35595730
The potential of pirtobrutinib in multiple B-cell malignancies.	2022	35747462

Patents

Sample Use Guides

In Vivo Use Guide

Recommended dosage: 200 mg orally once daily; swallow whole with water, with or without food. Do not cut, crush, or chew tablets.

Route of Administration: Oral

In Vitro Use Guide

One-hour incubation of pirtobrutinib decreased phospho-BTK (Y223) and downstream phospho-ERK (T202/Y204) levels in all cell lines starting at 0.01 uM in BTKWT and BTKC481R and at 0.1 uM in BTKC481S cells. Treatment with pirtobrutinib also decreased phospho-PLCγ2 (Y1217) levels at 0.01 uM in BTKWT and at 0.1 uM in BTKC481S.R Y223 autophosphorylation with IC50s of 8.45, 7.23, and 11.73 nM, respectively.

Substance Class	Chemical Created by `admin` on `Tue Apr 01 22:53:22 GMT 2025` Edited by `admin` on `Tue Apr 01 22:53:22 GMT 2025`
Record UNII	JNA39I7ZVB
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

JAYPIRCA

Preferred Name

English

PIRTOBRUTINIB

Official Name

English

1H-PYRAZOLE-4-CARBOXAMIDE, 5-AMINO-3-(4-(((5-FLUORO-2-METHOXYBENZOYL)AMINO)METHYL)PHENYL)-1-((1S)-2,2,2-TRIFLUORO-1-METHYLETHYL)-

Systematic Name

English

LY3527727

Code

English

5-AMINO-3-(4-((5-FLUORO-2-METHOXYBENZAMIDO)METHYL)PHENYL)-1-((2S)-1,1,1-TRIFLUOROPROPAN-2-YL)-1H-PYRAZOLE-4-CARBOXAMIDE

Systematic Name

English

LOXO-305

Code

English

PIRTOBRUTINIB [JAN]

Common Name

English

LY-3527727

Code

English

(S)-5-AMINO-3-(4-((5-FLUORO-2-METHOXYBENZAMIDO)METHYL)PHENYL)-1-(1,1,1-TRIFLUOROPROPAN-2-YL)-1H-PYRAZOLE-4-CARBOXAMIDE

Systematic Name

English

RXC-005

Code

English

PIRTOBRUTINIB [USAN]

Common Name

English

pirtobrutinib [INN]

Common Name

English

Pirtobrutinib [WHO-DD]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

758120