Chemical formula: C₁₈H₁₈FN₅O₂ Molecular mass: 355.144 g/mol PubChem compound: 135565923
Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1, the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, and anaplastic lymphoma kinase (ALK) with IC50 values of 0.05 to 1.04 nM.
Fusion proteins that include ROS1 or TRK domains can drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Repotrectinib has demonstrated in vitro and in vivo inhibition of cell lines expressing the targeted fusion oncogenes ROS1, TRKA, TRKB, TRKC, and corresponding mutations (ROS1G2032R, ROS1D2033N, TRKAG595R, TRKBG639R, TRKCG623R). Repotrectinib binds inside the boundary of the ATP-binding pocket and avoids steric interference from both solvent front and gatekeeper mutations.
Analysis of ECG data from 334 patients in the TRIDENT-1 phase 2 study, who received repotrectinib at the recommended dose (unknown prandial state), demonstrated that the upper limit of 90% confidence interval (CI) of the mean QTcF change from baseline (ΔQTcF) exceeded 10 milliseconds (ms) for a few time point estimates but remained <20 ms.
Patients with increased risk of QTc prolongation were not enrolled in TRIDENT-1.
The pharmacokinetic (PK) parameters for repotrectinib have been characterised in patients with NTRK gene fusion-positive solid tumours, ROS1-positive NSCLC, and in healthy subjects. Repotrectinib maximum concentration (Cmax) and area under the curve over time to infinity (AUC0-inf) increases were approximately dose proportional (but less than linear) with estimated slopes of 0.78 and 0.70, respectively over the single dose range of 40 mg to 240 mg. Steady state PK was time-dependent due to autoinduction of CYP3A4. The steady-state average concentration (Cavg) of 160 mg twice daily dosing regimen is similar to Cavg following 160 mg single dose administration.
Repotrectinib estimated steady state geometric mean (CV%) Cmax is 572 ng/mL (38.3%), Cmin is 158 ng/mL (57.7%), and Cavg (AUC0-12h divided by dosing interval) is 347 ng/mL (42.3%) for 160 mg twice a day.
Following oral administration of ascending single doses of repotrectinib ranging from 40 mg to 240 mg, repotrectinib exhibited rapid absorption with Cmax occurring at approximately 2-3 hours post dose under fasted conditions. The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%).
A high-fat, high-calorie meal (916 calories, 56% fat) increased repotrectinib AUC0-inf by 56% and Cmax by 149% following a single 160 mg oral dose (administered as 40 mg capsules). In another study, a high-fat, high-calorie meal increased AUC0-inf by 42% and Cmax by 110% following a single 160 mg oral dose (administered as 160 mg capsules). Similar increases (AUC0-inf by 36% and Cmax by 124%) were observed with a low-fat, low-calorie meal.
Repotrectinib peak concentration occurred at approximately 4 to 6 hours post a single oral dose of 40 mg to 160 mg under fed conditions (high-fat meal).
Binding of repotrectinib to human plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro. The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in cancer patients following a single 160 mg oral dose of repotrectinib.
Repotrectinib is primarily metabolised by CYP3A4 to form hydroxylated metabolites followed by secondary glucuronidation. No metabolite exceeded 10% of total circulating drug-related radioactivity.
Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4.
The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in cancer patients following a single 160 mg oral dose of repotrectinib. Based on the population PK (popPK) analysis, the single dose mean (SD) terminal half-life (t½) was estimated to be 68.6 (29.6) hours, and the steady state terminal t½ was estimated to be 44.5 (20.8) hours in cancer patients.
Following a single oral 160 mg dose of [14C] repotrectinib, 4.84% (0.56% as unchanged) of the radioactivity was recovered in urine and 88.8% (50.6% as unchanged) in faeces.
In the popPK analysis, mild (eGFR-CKD-EPI 60 to 90 mL/min, n=139) or moderate (eGFR-CKD-EPI 30 to 60 mL/min, n=27) renal impairment did not influence the clearance of repotrectinib. Repotrectinib has not been studied in patients with severe renal impairment (eGFR- CKD-EPI <30 mL/min).
In the popPK analysis, mild hepatic impairment (total bilirubin >1.0 to 1.5 times ULN or AST >ULN, n=59) did not influence the clearance of repotrectinib. Pharmacokinetics of repotrectinib have not been established in patients with moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment.
In the popPK analysis, no clinically relevant differences in the pharmacokinetics of repotrectinib were identified based on gender, age (18 years to 93 years), body weight (39.5 kg to 169 kg), or race (Asian and White) in adults.
PK data was available from paediatric patients 12 years and older (n=13, age 13 to 15 years, body weight 46.4 to 76.7 kg). Based on popPK simulations, adolescents 12 years and older have similar systemic exposure as that of adults when administered the adult dose of 160 mg once daily for 14 days, followed by 160 mg twice daily.
CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract), CYP2C8 and CYP2C9.
Other Metabolic Pathways: Repotrectinib inhibits UGT1A1.
Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, MATE1 and MATE2-K. Repotrectinib is a substrate for P-gp and a potential substrate for MATE2-K and BCRP.
Carcinogenicity studies with repotrectinib were not conducted.
Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.
Repotrectinib caused micronuclei formations via an aneugenic mechanism in human lymphoblastoid TK6 cells in vitro, and in bone marrow of rats in vivo at doses >100 mg/kg nominal dose. The exposure of animals at the no observed effect level (NOEL) for aneugenicity was approximately 3.4-fold human exposure at the recommended clinical dose (based on AUC).
In a preliminary embryo-foetal development study in rats, teratogenic and embryo-foetal effects (foetal external malformation of malrotated hindlimbs and decreased foetal weight) and maternal effects (skin scabbing and abrasions in cervical and thoracic regions and increased body weight) were observed in pregnant rats at exposures that were less than 2-fold human exposure at the recommended clinical dose.
Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general toxicology studies conducted in rats and monkeys at any dose level tested, which equated to exposures in rats of up to 2-fold and 2.6-fold in males and females, respectively, and exposures in monkeys that were below the human exposure at the recommended clinical dose.
Following repeat-dose oral administration of repotrectinib daily for up to 3 months, the main toxicities observed in rats at exposure levels <3-fold human exposure were skin scabs/ulcerations, CNS effects (i.e. ataxia, tremors), decreased RBC parameters, and bone marrow hypocellularity.
The main toxicities observed in monkeys at exposure margins below clinical exposure were emesis, watery faeces, minimal subacute/chronic inflammation and/or minimal to mild mucosal gland hyperplasia in the large intestines, and decreased RBC parameters. The skin ulcerations were considered secondary to NTRK inhibition resulting in loss of sensation and bodily injury.
Overall, juvenile rats were dosed and evaluated up to 58 days (starting on postnatal day [PND] 12 through PND 70) in repeat-dose toxicity studies. CNS-related mortality was observed at PND 13 to PND 15 (approximately equivalent to infant) at exposure levels ≥1.5-fold adolescent human exposure.
Decreased effects on growth (decreased body weight, food consumption and femur length) were observed at exposure levels ≥0.1-fold the adolescent human exposure.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.