Chemical formula: C₂₂H₂₁F₄N₅O₃ Molecular mass: 479.158 g/mol PubChem compound: 129269915
Pirtobrutinib is a reversible, noncovalent inhibitor of BTK. BTK is a signalling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK as well as BTK harboring C481 mutations leading to inhibition of BTK kinase activity.
The effect of a single 900 mg dose of pirtobrutinib on the corrected QT (QTc) interval was evaluated in a study with placebo and positive controls in 30 healthy subjects. The selected dose is equivalent to approximately 2 times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily. Pirtobrutinib had no clinically meaningful effect on the change in QT corrected for heart rate using Fridericia’s formula (QTcF) interval (i.e., >10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.
The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Doses ranged from 25 mg to 300 mg once daily (0.125 to 1.5 times the recommended dosage of 200 mg once daily), up to single doses of 900 mg. Increases in plasma exposure were approximately dose proportional. Steady state was achieved within 5 days of once daily dosing, and in cancer patients the mean [coefficient of variation (CV
The mean (CV %) steady-state AUC and Cmax were 91 100 h*ng/mL (41
At the recommended dosage, pirtobrutinib achieves pharmacokinetic exposures that can exceed the BTK IC96 at trough and thus deliver tonic BTK target inhibition throughout the once daily dosing period, regardless of the intrinsic rate of BTK turnover.
The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5% in healthy subjects. The median time to reach peak plasma concentration (tmax) is approximately 2 hours in both cancer patients and healthy subjects. There is no pH dependency for absorption.
A high-fat, high-calorie meal administered to healthy subjects decreased the Cmax of pirtobrutinib by 23% and delayed tmax by 1 hour. There was no effect on pirtobrutinib AUC. Pirtobrutinib can be taken with or without food.
The mean apparent central volume of distribution of pirtobrutinib is 29.0 L in cancer patients. The plasma protein binding is 96% and was independent of concentration between 0.5 and 50 µM. In plasma from healthy subjects and subjects with severe renal impairment the protein binding was 96%. Mean blood-to-plasma ratio is 0.79.
Hepatic metabolism is the main route of clearance for pirtobrutinib. Pirtobrutinib is metabolised to several inactive metabolites by CYP3A4, UGT1A8 and UGT1A9. There was no clinically meaningful impact of CYP3A modulation on pirtobrutinib exposures.
Pirtobrutinib inhibits CYP2C8, CYP2C9 and CYP3A4 in vitro and minimally inhibits CYP1A2, CYP2B6, CYP2C19 or CYP2D6 at 60 µM. In vitro pirtobrutinib induces CYP3A4, CYP3A5, CYP2C19, and CYP2B6.
Pirtobrutinib minimally inhibits UGT1A1 in vitro with an IC50 = 18 µM.
In vitro studies indicated that pirtobrutinib is a substrate of P-gp and BCRP.
Pirtobrutinib is an in vitro inhibitor of P-gp and BCRP. Pirtobrutinib affected the PK of digoxin, a P-gp substrate, and rosuvastatin, a BCRP substrate, in clinical studies.
The mean apparent clearance of pirtobrutinib is 2.04 L/h with an effective half-life of approximately 19 hours. Following a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in faeces (18% unchanged) and 57% in urine (10% unchanged).
Based on a population pharmacokinetic analysis in patients with cancer, age (range 27-95 years), race, gender, and body weight (range 35.7-152.5 kg) had no clinically meaningful effect on the exposure of pirtobrutinib.
In a population PK analysis of cancer patients, patients with mild (eGFR 60 to <90 ml/min) or moderate renal impairment (eGFR 30 to <60 ml/min), pirtobrutinib clearance was 16% to 27% lower compared to clearance in patients with normal renal function, resulting in expected exposure of AUC = 94 100 ng*h/mL and Cmax = 6 680 ng/mL in patients with mild renal impairment (16-19% higher compared to patients with normal renal function) and AUC = 108 000 ng*h/mL and Cmax = 7 360 ng/mL in patients with moderate renal impairment (28 to 36% higher compared to patients with normal renal function).
In a clinical pharmacology study of otherwise healthy volunteers, apparent clearance was 35% lower in four participants with severe renal impairment (eGFR 15 to <30 ml/min) compared to eight participants with normal renal function (eGFR ≥90 ml/min), resulting in exposures of AUC0-inf = 115 000 ng*h/mL and Cmax = 2 980 ng/mL (62% higher and 7% lower, respectively, compared to normal renal function).
Patients with end-stage renal disease receiving dialysis were not studied.
There were no clinically significant differences in the PK of pirtobrutinib for any degree of hepatic impairment (by Child-Pugh A, B, and C or any total bilirubin and any AST). In a dedicated hepatic impairment study mean AUC and Cmax of pirtobrutinib were similar between subjects with mild hepatic impairment (Child-Pugh A) and subjects with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh B) the AUC was 15% lower compared to normal hepatic function and the Cmax was similar. In subjects with severe hepatic impairment (Child-Pugh C) the AUC of pirtobrutinib was 21% lower and mean Cmax was 24% lower compared to subjects with normal hepatic function. The fraction unbound (fu) for pirtobrutinib in subjects generally increased as the severity of hepatic impairment increased. Therefore, after correcting pirtobrutinib PK exposure parameters with fu, there was no clinically significant difference observed in the unbound pirtobrutinib PK exposure parameters (AUCu and Cmax,u) between subjects with any degree of hepatic impairment and normal hepatic function.
No pharmacokinetic studies were performed with pirtobrutinib in patients under 18 years of age.
In the repeat-dose studies decreased T-cell dependent antibody response in rats (at 0.69-fold human exposure at the recommended dose of 200 mg based on AUC) and minimal to mild corneal lesions in dogs (at 0.42-fold human exposure) were observed.
Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in two in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib had no effect in an in vivo rat bone marrow micronucleus assay at doses up to 2 000 mg/kg (single dose), which is approximately 11-fold higher exposure (considering unbound Cmax value in female animals) than human exposure at 200 mg.
Carcinogenicity studies have not been conducted with pirtobrutinib.
In animal reproduction studies, administration of pirtobrutinib to pregnant rats during organogenesis resulted in decreased foetal weight, embryo-foetal mortality, and foetal malformations at maternal exposures 3.0-fold human exposure at the recommended dose of 200 mg based on AUC.
No fertility studies have been conducted with pirtobrutinib. In repeat-dose toxicity studies of up to 3 months duration, pirtobrutinib had no effect on male reproductive organs at 0.69-fold and 0.42-fold human exposure in rats and dogs, respectively, at the recommended dose of 200 mg based on AUC. Pirtobrutinib had no effect on female reproductive organs at 4.0-fold and 0.42-fold human exposure in rats and dogs, respectively.
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