Appl. No.: N216059 Dosage Form: Tablet Route: Oral Strength: 50 mg and 100 mg
Applicant
Holder: Loxo Oncology Inc.
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.
Mantle
Cell Lymphoma
Chronic
Lymphocytic Leukemia / Small Lymphocytic
Lymphoma
API
Pirtobrutinib is a white to
practically white to yellow to brown solid. The aqueous solubility of
pirtobrutinib is considered practically insoluble, or insoluble, across the pH
1 to pH 7 range.
Dosage Form
Pirtobrutinib tablets are supplied as
50 mg or 100 mg film-coated, debossed tablets for oral administration.
Composition / Excipients
Each tablet contains inactive
ingredients of croscarmellose sodium, hypromellose acetate succinate, lactose
monohydrate, magnesium stearate, microcrystalline cellulose and silicon
dioxide. The tablet film coating material contains FD&C Blue #2, hypromellose,
titanium dioxide and triacetin.
Dosage Range
The recommended dosage of JAYPIRCA is
200 mg orally once daily until disease progression or unacceptable toxicity.
PK
The pharmacokinetics of pirtobrutinib
were characterized in healthy subjects and in patients with cancer.
Pirtobrutinib exposure (AUC) and Cmax increases
proportionally following single oral doses ranging from 300 mg to 800 mg (1.5
to 4 times the approved recommended dosage) and once daily doses ranging
from 25 – 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was
achieved within 5 days of once daily dosing, and the mean (CV%) accumulation
ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.
Absorption
The absolute bioavailability of
pirtobrutinib after a single oral 200 mg dose is 85.5% (range 75.9% to 90.9%).
The median time (range) to reach peak plasma concentration (tmax)
is approximately 2 hours (0.833 to 4.15 hours).
Effect of Food
A high-fat meal decreased the Cmax of pirtobrutinib by 23% and delayed tmax
by 1 hour. There was no effect on pirtobrutinib AUC.
Metabolism
Pirtobrutinib
is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and
UGT1A9, in vitro.
Following
a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of
the dose was recovered in feces (18% unchanged) and 57% in urine (10%
unchanged).
Orange Book Patent
and Exclusivity
10342780 (Exp Date: 12/16/2036): A chemical
10464905 (Exp Date: 12/16/2036): A method of treating cancer in a patient in need
thereof, the method comprising: (a) detecting a cancer modulated by BTK
signaling in a patient; and
(b) administering to the patient a therapeutically effective amount of a
compound (please check the patent for details.)
10695323
(Exp Date: 12/16/2036): a chemical
10918622
(Exp Date: 12/16/2036): A method of treating B-cell non-Hodgkin lymphoma
"Ibrutinib and acalabrutinib irreversibly inhibit BTK by covalently modifying a cysteine in the ATP binding pocket required for enzymatic activity. Recovery from platelet dysfunction caused by irreversible BTKi is dependent on platelet turnover, which has a half-life of 7 to 10 days. Pirtobrutinib also targets the ATP binding pocket but binds non-covalently and inhibition is reversible. Recovery of normal platelet function is therefore likely to be determined by drug wash-out and not platelet turnover. In order to investigate how wash-off of BTKi influenced platelet function, we measured P-selectin exposure as a marker of α-granule secretion evoked by CRP-XL or TRAP-6 in PRP or 1 hour after washing the platelets. There was no difference in P-selectin exposure evoked by TRAP-6, except a small but significant decrease after washing in patients receiving acalabrutinib, possibly caused by a small loss in responsiveness during the washing process. We found that p-selectin exposure evoked by CRP-XL recovered in washed platelets but not in PRP from patients receiving pirtobrutinib. There was no significant difference for patients receiving acalabrutinib or ibrutinib. We further investigated reversibility by treating whole blood samples from healthy donors with the BTKi and measuring thrombus formation with or without washing off the inhibitors. After pirtobrutinib was washed off, platelet function was not significantly different to vehicle-treated samples, but thrombus formation in ibrutinib- and acalabrutinib-treated samples remained impaired."
- Alexander P Bye et al. Pirtobrutinib results in reversible platelet dysfunction compared to ibrutinib and acalabrutinib, Haematologica. 2023 May 1; 108(5): 1429–1435.)
