Pirtobrutinib

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 Cmax of 91300 h?ng/mL and 6460 ng/mL, respectively. On day 8 of cycle 1, pirtobrutinib had an AUC0-24 of 81800 h?ng/mL and a Cmax of 3670 ng/mL. After approximately 2 hours, pirtobrutinib reaches peak plasma concentration (tmax).
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 Cmax of pirtobrutinib by 23%, delayed tmax by 1 hour and had no effects on the AUC.

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. 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.

Description

Pirtobrutinib, or LOXO-305 and LY 3527727, is a Bruton's tyrosine kinase (BTK) inhibitor and antineoplastic agent. Pirtobrutinib showed promising initial efficacy in pts with pretreated Richter transformation with extremely poor prognosis, including in patients who had received prior chemoimmunotherapy and covalent BTK inhibitors. Pirtobrutinib is a highly selective and potent non-covalent BTK inhibitor (BTKi) with high oral bioavailability and a long half-life, resulting in robust BTK target coverage even in high-grade malignancies with high BTK protein turnover.

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. 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. However, other mutations may confer resistance to non-covalent BTK inhibitors such as pirtobrutinib.
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.

Indications

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.

Pharmacokinetics

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. 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. 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. At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC96.
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. 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.

Metabolism

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