Pirtobrutinib

Identification

Summary

Pirtobrutinib is a kinase inhibitor used to treat relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy.

Brand Names

Jaypirca

Generic Name

Pirtobrutinib

DrugBank Accession Number

DB17472

Background

Pirtobrutinib is a small molecule and a highly selective non-covalent inhibitor of Bruton’s tyrosine kinase (BTK). Its high selectivity has been associated with lower discontinuation rates due to adverse events and a lower incidence of atrial fibrillation.¹ Unlike BTK covalent inhibitors, such as ibrutinib, that bind to the cysteine 481 (Cys481) amino acid within the active site of BTK, the inhibitory activity of pirtobrutinib is maintained even in the presence of Cys481 mutations. Although the mechanisms of resistance to covalent BTK inhibitors have not been fully elucidated, it appears that the presence of Cys481 mutations is the most common reason for resistance to covalent BTK inhibitors.^1,4,6 However, other mutations may confer resistance to non-covalent BTK inhibitors such as pirtobrutinib.⁵

In January 2023, the use of pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy was approved under the FDA's Accelerated Approval pathway.^6,7

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Pirtobrutinib (DB17472)

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Weight

Average: 479.436
Monoisotopic: 479.158052208

Chemical Formula

C₂₂H₂₁F₄N₅O₃

Synonyms

• (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide
• 1h-pyrazole-4-carboxamide, 5-amino-3-(4-(((5-fluoro-2-methoxybenzoyl)amino)methyl)phenyl)-1-((1s)-2,2,2-trifluoro-1-methylethyl)-
• 5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-((2s)-1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide

External IDs

• LOXO-305
• LY-3527727
• LY3527727
• RXC-005

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Pharmacology

Indication

Pirtobrutinib is 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.⁶

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Chronic lymphocytic leukemia		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	••••••
Treatment of	Refractory mantle cell lymphoma (mcl)		••••••••••••	•••••	••••• •• ••••• •• •••••••• •••••••	••••••
Treatment of	Relapsed mantle cell lymphoma		••••••••••••	•••••	••••• •• ••••• •• •••••••• •••••••	••••••
Treatment of	Small lymphocytic lymphoma		••••••••••••	•••••	•• ••••• ••• ••••• •••••••• •••••••••	••••••

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Pharmacodynamics

Pirtobrutinib is a non-covalent inhibitor of Bruton’s tyrosine kinase (BTK) with more than 300-fold selectivity for BTK over 98% of other kinases.^1,6 In vivo murine studies suggest that pirtobrutinib has an efficacy similar to ibrutinib with BTK wild-type tumor cells but an improved efficacy in BTK Cys481 mutant cells.¹ Pirtobrutinib has shown efficacy against different B-cell malignancies and is effective in patients that are intolerant of irreversible BTK inhibitors or have developed a disease resistant to these covalent inhibitors.² At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC₉₆.⁶

In healthy subjects given a single 900 mg dose (concentration 2 times higher than the steady state at the recommended dosage), pirtobrutinib did not have a clinically meaningful effect on the change in QTcF interval, and there was no relationship between pirtobrutinib exposure and change in QTc interval.⁶ The use of pirtobrutinib may lead to fatal and serious infections, hemorrhage, cytopenias, atrial fibrillation and atrial flutter. Patients should also be warned about the development of second primary malignancies.⁶

Mechanism of action

Bruton’s tyrosine kinase (BTK) is a tyrosine kinase located in the cytoplasm that is recruited to the cytoplasm upon activation. In B-cells, BTK participates in the activation of B-cell antigen receptor (BCR) signaling and cytokine receptor pathways, both critical for B-cell development, function, adhesion and migration. Therefore, the inhibition of BTK is a valuable target for the treatment of B-cell cancers.^3,6 Pirtobrutinib binds to Bruton’s tyrosine kinase (BTK) in a non-covalent manner and inhibits its activity. Unlike other BTK inhibitors that bind covalently to the active site of BTK, the inhibitory activity of pirtobrutinib is maintained even in the presence of mutations in this region, such as the presence of Cys481.^1,6 In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation.⁶

Target	Actions	Organism
ATyrosine-protein kinase BTK	inhibitor	Humans

Absorption

With single oral doses between 300 mg and 800 mg (1.5 to 4 times the approved recommended dose) and once daily doses between 25 mg and 300 mg (0.125 to 1.5 times the recommended dose), pirtobrutinib follows a dose-proportional pharmacokinetic profile. Within 5 days of once-daily dosing, pirtobrutinib reached steady-state concentration, with an accumulation ratio of 1.63 based on AUC after 200 mg dosages. With the recommended dose, pirtobrutinib has a steady-state AUC and C_max of 91300 h⋅ng/mL and 6460 ng/mL, respectively. On day 8 of cycle 1, pirtobrutinib had an AUC_0-24 of 81800 h⋅ng/mL and a C_max of 3670 ng/mL. After approximately 2 hours, pirtobrutinib reaches peak plasma concentration (t_max).⁶

After a single oral dose of 200 mg, pirtobrutinib reaches an absolute bioavailability of 85.5%. The administration of a high-fat, high-calorie meal to healthy subjects did not have a clinically significant effect on the pharmacokinetics of pirtobrutinib. A high-fat meal decreased the C_max of pirtobrutinib by 23%, delayed t_max by 1 hour and had no effects on the AUC.⁶

Volume of distribution

Pirtobrutinib has an apparent central volume of distribution of 32.8 L.⁶

Protein binding

The human protein binding of pirtobrutinib is 96%, independent of in vitro concentration. Pirtobrutinib has a blood-to-plasma ratio of 0.79.⁶

Metabolism

In vitro studies suggest that pirtobrutinib is mainly metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9.⁶

Route of elimination

Pirtobrutinib is mainly excreted in urine and feces. In healthy subjects given a single dose of 200 mg of radiolabeled pirtobrutinib, 57% of the dose was recovered in urine (10% unchanged), and 37% was recovered in feces (18% unchanged).⁶

Half-life

Pirtobrutinib has an effective half-life of approximately 19 hours.⁶

Clearance

Pirtobrutinib has an apparent clearance of 2.02 L/h.⁶

Adverse Effects

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Toxicity

Toxicity information regarding pirtobrutinib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hemorrhage, cytopenias, atrial fibrillation and atrial flutter.⁶ Symptomatic and supportive measures are recommended. In vivo carcinogenicity studies have not been conducted with pirtobrutinib. A bacterial mutagenicity (Ames) assay found that pirtobrutinib was not mutagenic, and in vitro micronucleus assays using human peripheral blood lymphocytes found that pirtobrutinib was aneugenic. Up to 2000 mg/kg, pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay.⁶

Pathways

Not Available

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Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Pirtobrutinib can be increased when it is combined with Abametapir.
Abatacept	The risk or severity of adverse effects can be increased when Abatacept is combined with Pirtobrutinib.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Pirtobrutinib.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Pirtobrutinib.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Pirtobrutinib.

Food Interactions

• Take at the same time every day. Pirtobrutinib should be taken at approximately the same time each day with or without food.
• Take with or without food. High-fat, high-calorie meals do not have a clinically significant effect in the pharmacokinetics of pirtobrutinib.

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International/Other Brands

Jaypirca (Eli Lilly)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Jaypirca	Tablet, coated	100 mg/1	Oral	Eli Lilly and Company	2023-01-27	Not applicable
Jaypirca	Tablet, coated	50 mg/1	Oral	Eli Lilly and Company	2023-01-27	Not applicable

Categories

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• BCRP/ABCG2 Inhibitors
• BCRP/ABCG2 Substrates
• Bruton's tyrosine kinase (BTK) inhibitors
• Cancer immunotherapy
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2B6 Inhibitors
• Cytochrome P-450 CYP2B6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (weak)
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (moderate)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inducers
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inducers
• Cytochrome P-450 CYP3A4 Inducers (strength unknown)
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A5 Inducers
• Cytochrome P-450 CYP3A5 Inducers (strength unknown)
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Enzyme Inhibitors
• Immunosuppressive Agents
• Immunotherapy
• Kinase Inhibitor
• Myelosuppressive Agents
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• Protein Kinase Inhibitors
• Tyrosine Kinase Inhibitors
• UGT1A9 Substrates

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

JNA39I7ZVB

CAS number

2101700-15-4

InChI Key

FWZAWAUZXYCBKZ-NSHDSACASA-N

InChI

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

IUPAC Name

5-amino-3-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide

SMILES

COC1=C(C=C(F)C=C1)C(=O)NCC1=CC=C(C=C1)C1=NN([C@@H](C)C(F)(F)F)C(N)=C1C(N)=O

References

Synthesis Reference

Guisot, N. (2017). Compounds useful as kinase inhibitors (WO 2017/103611 A1). World Intellectual Property Organization. https://patentimages.storage.googleapis.com/d7/16/21/9300e49071a21a/WO2017103611A1.pdf

General References

1. Jensen JL, Mato AR, Pena C, Roeker LE, Coombs CC: The potential of pirtobrutinib in multiple B-cell malignancies. Ther Adv Hematol. 2022 Jun 16;13:20406207221101697. doi: 10.1177/20406207221101697. eCollection 2022. [Article]
2. Aslan B, Kismali G, Iles LR, Manyam GC, Ayres ML, Chen LS, Gagea M, Bertilaccio MTS, Wierda WG, Gandhi V: Pirtobrutinib inhibits wild-type and mutant Bruton's tyrosine kinase-mediated signaling in chronic lymphocytic leukemia. Blood Cancer J. 2022 May 20;12(5):80. doi: 10.1038/s41408-022-00675-9. [Article]
3. Alu A, Lei H, Han X, Wei Y, Wei X: BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J Hematol Oncol. 2022 Oct 1;15(1):138. doi: 10.1186/s13045-022-01353-w. [Article]
4. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5. [Article]
5. Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, Durham BH, Penson A, Witkowski MT, Lu SX, Bourcier J, Hogg SJ, Erickson C, Cui D, Cho H, Singer M, Totiger TM, Chaudhry S, Geyer M, Alencar A, Linley AJ, Palomba ML, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O: Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors. N Engl J Med. 2022 Feb 24;386(8):735-743. doi: 10.1056/NEJMoa2114110. [Article]
6. FDA Approved Drug Products: JAYPIRCA (pirtobrutinib) tablets for oral use [Link]
7. BioSpace: U.S. FDA Approves Jaypirca (pirtobrutinib), the First and Only Non-Covalent (Reversible) BTK Inhibitor, for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma After at Least Two Lines of Systemic Therapy, Including a BTK Inhibitor [Link]

External Links

ChemSpider

114875989

RxNav

2629338

ChEMBL

CHEMBL4650485

PDBe Ligand

Y7W

Wikipedia

Pirtobrutinib

PDB Entries

8fll / 8fln

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Recruiting	Treatment	B-Cell Leukemia / Chronic Lymphocytic Leukemia / Lymphocytic Leukemia / Small Lymphocytic Lymphoma	1
3	Recruiting	Treatment	Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma	3
3	Recruiting	Treatment	Mantle Cell Lymphoma (MCL)	1
2	Active Not Recruiting	Treatment	B-Cell Chronic Lymphocytic Leukemia / B-Cell Lymphoma / Diffuse Large B-Cell Lymphoma (DLBCL) / Lymphocytic Leukemia / Mantle Cell Lymphoma (MCL) / Marginal Zone B-Cell Lymphoma / Non-Hodgkin's Lymphoma (NHL)	1
2	Not Yet Recruiting	Treatment	Mantle Cell Lymphoma (MCL)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, coated	Oral	100 mg/1
Tablet, coated	Oral	50 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US10918622	No	2021-02-16	2036-12-16
US10695323	No	2020-06-30	2036-12-16
US10464905	No	2019-11-05	2036-12-16
US10342780	No	2019-07-09	2036-12-16

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Practically insoluble or insoluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.00384 mg/mL	ALOGPS
logP	3.17	ALOGPS
logP	3.35	Chemaxon
logS	-5.1	ALOGPS
pKa (Strongest Acidic)	13.27	Chemaxon
pKa (Strongest Basic)	2.43	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	125.26 Å2	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	127.89 m3·mol-1	Chemaxon
Polarizability	45.01 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Tyrosine-protein kinase BTK

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein tyrosine kinase activity

Specific Function

Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately le...

Gene Name

BTK

Uniprot ID

Q06187

Uniprot Name

Tyrosine-protein kinase BTK

Molecular Weight

76280.71 Da

References

1. Jensen JL, Mato AR, Pena C, Roeker LE, Coombs CC: The potential of pirtobrutinib in multiple B-cell malignancies. Ther Adv Hematol. 2022 Jun 16;13:20406207221101697. doi: 10.1177/20406207221101697. eCollection 2022. [Article]
2. Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M: Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5. [Article]
3. FDA Approved Drug Products: JAYPIRCA (pirtobrutinib) tablets for oral use [Link]

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Drug created at January 30, 2023 16:16 / Updated at December 07, 2023 08:36