Molecular mass: 533.612 g/mol
Pralsetinib is a potent protein kinase inhibitor that selectively targets oncogenic RET fusions (KIF5BRET and CCDC6-RET). In NSCLC, RET fusions are one of the main oncogenic drivers. In vitro, pralsetinib inhibited several oncogenic RET fusions more potently than off-target kinases at clinically relevant concentrations (e.g. 81-fold selectivity over VEGFR2). Pralsetinib exhibited anti-tumour activity in cultured cells and animal tumour implantation models representing multiple tumour types harbouring oncogenic RET fusions (KIF5B-RET, CCDC6-RET).
The QT interval prolongation potential of pralsetinib was assessed in 34 patients with RET fusionpositive solid tumours administered at 400 mg once daily in a formal ECG sub-study.
In patients receiving pralsetinib in the ARROW study, QT prolongation was reported. Therefore, dose interruption or modification may be required in patients treated with pralsetinib.
Pralsetinib Cmax and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose); pharmacokinetics was linear in the dose range of 200 and 400 mg in healthy volunteers. Pralsetinib plasma concentrations reached steady state by 3 to 5 days.
At the recommended dose of 400 mg once daily under fasting conditions, the mean steady state Cmax of pralsetinib was 2830 ng/mL and the mean steady state area under the concentration-time curve (AUC0-24h) was 43900 h•ng/mL. The mean accumulation ratio was ~2-fold after repeated dosing.
The median time to peak concentration (Tmax) ranged from 2.0 to 4.0 hours following single doses of pralsetinib 60 mg to 600 mg (0.15 to 1.5 times the approved recommended dose). The absolute bioavailability of pralsetinib has not been determined.
Following administration of a single dose of 200 mg pralsetinib with a high-fat meal (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC0-∞ was increased by 122% (96%, 152%), and the median Tmax was delayed from 4 to 8.5 hours, compared to the fasted state.
The mean apparent volume of distribution of pralsetinib is 3.8 L/kg (268 L). Plasma protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.
Pralsetinib is primarily metabolised by CYP3A4 and UGT1A4, and to a lesser extent by CYP2D6 and CYP1A2 in vitro.
Following a single oral dose of approximately 310 mg of radiolabelled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) were detected in small to trace amounts (~5%).
The mean plasma elimination half-life of pralsetinib was 14.7 hours following a single dose of 400 mg (the recommended dose) pralsetinib and 22.2 hours following multiple doses of 400 mg pralsetinib. The steady state mean apparent oral clearance of pralsetinib (CL/F) is 9.1 L/h.
Following a single oral dose of radiolabelled pralsetinib to healthy subjects, 72.5% of the radioactive dose was recovered in faeces (66% as unchanged) and 6.1% in urine (4.8% as unchanged).
In vitro studies indicate that pralsetinib is a time-dependent inhibitor of CYP3A4/5 at clinically relevant concentrations. Pralsetinib may have the potential to inhibit or induce CYP2C8, CYP2C9, and CYP3A4/5 at clinically relevant concentrations.
In vitro studies indicate that pralsetinib may have the potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and MATE2-K at clinically relevant concentrations. Pralsetinib is a substrate of P-gp.
In vitro studies indicate that pralsetinib may be a potential substrate of P-glycoprotein (P-gp) and BCRP at clinically relevant concentrations.
No clinically relevant differences in the pharmacokinetics of pralsetinib were observed based on age (19 to 87 years), sex, race (White, Black, or Asian), body weight (34.9 to 128 kg), mild to moderate (CLCR 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST). The effect of severe renal impairment (CLCR 15 to 29 mL/min), end-stage renal disease (CLCR <15 mL/min), or moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST) on the pharmacokinetics of pralsetinib is unknown. Hence, no dose modifications are needed in the above mentioned special populations.
In studies of up to 13 weeks duration in rats and cynomolgus monkeys, the primary findings at exposures similar to steady state human exposures (AUC) at 400 mg once daily in patients with advanced NSCLC included physeal dysplasia in the rat (2 times margin) and haematological effects (1 times margin) in both species. Additional adverse findings at higher exposures include degenerative changes in male and female reproductive organs (2 times margin) and increases in blood phosphorus with corresponding mineralization in soft tissues in rats (≥2 times margin), and myocardial haemorrhage in rats (4.4 times margin). Increased blood pressure was observed in rats after a single dose of 25 mg/kg (2 times). The No-Observed-Adverse-Effect-Level (NOAEL) of pralsetinib in the 13-week studies was 10 mg/kg/day in both species, corresponding to exposure (AUC) margins of 1 times relative to the human exposures.
Regarding local exposure and toxicity, there was no evidence of gastrointestinal disturbance in either species up to the NOAEL dose of 10 mg/kg (0.9 times human margin). At higher doses in monkeys, gastrointestinal ulcerations and haemorrhage were observed.
In an embryo-fetal development study, administration of pralsetinib to rats during the period of organogenesis was teratogenic and embryotoxic at exposures below the steady-state human clinical exposure (AUC) at 400 mg once daily dose. Malformations, including visceral (primarily kidney and ureter) and skeletal (vertebral, rib, costal cartilage, and vertebral central anomalies) were observed at approximately 0.2-fold of the human exposure. Postimplantation loss occurred at 0.5-fold of the human exposure, and increased to 100% incidence at 1.5-fold of human exposure.
In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats pralsetinib did not have an effect on male or female mating performance or ability to become pregnant. However, consistent with the findings of the embryofetal development toxicology study there was post-implantation loss at doses as low as 5 mg/kg (approximately 0.3 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). At the 20 mg/kg dose level (approximately 2.5-3.6 times the human exposure) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions).
In a 13-week repeat-dose toxicology study, male rats exhibited microscopic evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥10 mg/kg/day, approximately 0.9 times the human exposure based on AUC at the clinical dose of 400 mg. No findings were noted in the reproductive organs in a 13-week repeated-dose toxicology study in monkeys at dose levels up to 10 mg/kg/day (approximately 1 times the human exposure at the 400 mg once daily dose).
Pralsetinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was negative in both in vitro human lymphocyte chromosome aberration assay and in vivo rat bone marrow micronucleus tests.
Carcinogenicity studies with pralsetinib have not been conducted.
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