Chemical formula: C₁₄H₁₃ClF₆N₆ Molecular mass: 414.079 g/mol PubChem compound: 117817422
Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes. In patients with astrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of the oncogenic metabolite 2-hydroxyglutarate (2-HG), resulting in impaired cellular differentiation contributing to oncogenesis. Inhibition of the IDH1- and IDH2-mutated proteins by vorasidenib inhibits the abnormal production of 2-HG leading to differentiation of malignant cells and a reduction in their proliferation. Pre-clinical studies investigating the ability of vorasidenib to decrease tumour size were not performed.
A therapeutic daily dose of vorasidenib was observed to decrease 2-HG tumour concentrations in subjects with IDH1 or IDH2 mutated glioma.
The pharmacokinetics of vorasidenib have been characterised in patients with low-grade glioma with an IDH1 or IDH2 mutation and in healthy subjects. The pharmacokinetic profile of vorasidenib is similar between patients with low-grade glioma and healthy subjects.
After a single 40 mg oral dose, the median time to Cmax (Tmax) for vorasidenib was 2.0 hours, the geometric mean Cmax was 75.4 ng/mL (CV%: 44), and the geometric mean AUC was 2,860 hr*ng/mL (CV%: 56). At steady-state, vorasidenib geometric mean Cmax was 133 ng/mL (CV%: 73) and geometric mean AUC was 1,988 hr*ng/mL (CV%: 95). In most patients, a second plasma concentration peak occurred within 24 hours after drug administration but was lower than the observed Cmax at 2 hours post-dose. Although absolute bioavailability has not been directly determined, the absorption of vorasidenib is estimated to be moderate to high for the 40 mg film-coated tablets.
Accumulation ratios were approximately 3.8 for Cmax and 4.4 for AUC. Steady-state plasma levels were reached after 2 to 3 weeks of once-daily dosing.
The mean Cmax and AUC of vorasidenib increased by 3.1-fold and 1.4-fold, respectively, when vorasidenib was administered with a high-fat meal. Administration of vorasidenib with a low-fat meal resulted in increases in vorasidenib Cmax and AUC of 2.3- and 1.4-fold, respectively.
Vorasidenib has a mean apparent volume of distribution of 3,930 L (CV%: 40). The vorasidenib volume of distribution following a single 0.1 mg IV microdose is 1,110 L. The bound plasma protein fraction for vorasidenib and AGI-69460 was 97% and 87%, respectively. Both vorasidenib and AGI-69460 exhibit preferential binding to serum albumin over alpha-1 acid glycoprotein. Vorasidenib blood to plasma ratio is 0.87, AGI-69460 blood to plasma ratio is 1.38, and vorasidenib brain tumour to plasma concentration ratio is 1.6.
Vorasidenib is primarily metabolised by CYP1A2 with negligible to minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Non-CYP pathways may contribute up to 30% of vorasidenib liver metabolic clearance.
AGI-69460 is a downstream active metabolite of vorasidenib. After a single 40 mg vorasidenib oral dose, the observed Tmax for metabolite AGI-69460 was 336 hours, the observed geometric mean Cmax was 3.32 ng/mL (CV%: 55.6), and the geometric mean AUC0-t was 1,172 hr*ng/mL (CV%: 61). At steady-state, geometric mean AGI-69460 Cmin,ss was 111 ng/mL (CV%: 58) and geometric mean AUC0-4 at cycle 2 day 1 was 190 hr*ng/mL (CV%: 90).
In vitro, vorasidenib has a strong induction effect on sensitive CYP3A4 substrates and a moderate induction effect on sensitive CYP2B6 and CYP2C19 substrates.
In vitro data indicate that vorasidenib is an inhibitor of BCRP. Vorasidenib does not inhibit P-glycoprotein (P-gp) and hepatic transporter organic anion transporting polypeptide (OATP)1B1. In vitro, AGI-69460 is an inhibitor of BCRP and OATP1B3.
Vorasidenib is not a substrate of P-gp, BCRP, or hepatic transporters OATP1B1 and OATP1B3.
Approximately 89% of the administered vorasidenib radioactive dose, using a powder-in-capsule formulation with an absolute bioavailability of < 34%, was recovered over 44 days, with 85% in faeces and 4.5% in urine. Most of the administered radioactivity that was recovered in faeces was unchanged vorasidenib (55%) while no unchanged vorasidenib was detected in urine.
The mean terminal half-life of vorasidenib is 238 hours (CV%: 57), the effective half-life is 63.2 hours (CV%: 75) and the mean apparent clearance is 14.0 L/h (CV%: 56).
Following administration of vorasidenib, vorasidenib Cmax and AUC increases in a proportional manner between 10 and 40 mg.
No clinically meaningful effects on the pharmacokinetics of vorasidenib were observed in older patients up to 75 years.
Renal impairment (eGFR >40 mL/min/1.73 m²) had no clinically significant effect on the pharmacokinetics of vorasidenib. The pharmacokinetics of vorasidenib in patients with eGFR ≤40 mL/min/1.73 m² or renal impairment requiring dialysis are unknown.
Moderate hepatic impairment (Child-Pugh class B) had no clinically significant effects on vorasidenib and AGI-69460 pharmacokinetics. There were no clinically relevant changes in total or free (unbound) vorasidenib concentrations (similar vorasidenib Cmax values and an increase of 26.0% in vorasidenib AUC0-t were observed, while decreased AGI-69460 exposure was observed) in patients with moderate hepatic impairment following a single oral dose of 20 mg vorasidenib. The pharmacokinetics of vorasidenib and AGI-69460 in patients with severe hepatic impairment (Child-Pugh class C) are unknown.
No clinically significant effects on the pharmacokinetics of vorasidenib were observed based on age (16 to 75 years), race, ethnicity and body weight (43.5 to 168 kg). Female patients were observed to have a 1.6-fold higher vorasidenib exposure as compared to male patients.
Pharmacokinetic data demonstrated that age had no clinically meaningful effect on the pharmacokinetics of vorasidenib. The exposure of vorasidenib is expected to be similar between adults and adolescent patients aged 12 years and older
The main target toxicities identified during repeat-dose toxicity studies concern liver, gastrointestinal tract, skin, kidney, skeletal muscle, reproductive organs and mammary gland.
Vorasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays. AGI-69460, its major circulating metabolite, was not genotoxic in the Ames assay, the in vitro human lymphocyte micronucleus assay, and the in vivo rat bone marrow micronucleus and Comet assays.
In the 13-week study in monkeys, Kupffer cell hyperplasia were observed at primary necropsy and worsened after recovery period at 8-fold the clinical exposure. In addition, findings from rat toxicity studies suggested hormonal perturbation. Such findings may be suggestive of potential carcinogenic risk. Carcinogenicity studies have not been conducted yet with vorasidenib.
Fertility studies in animals have not been conducted with vorasidenib. Effects on reproductive organs were noted during repeat-dose toxicity studies after administration of vorasidenib in rats. Adverse effects in female reproductive organs included atrophy of the ovaries, uterus, cervix and vagina and oestrous cycle variations. In male rats, effects were noted on the epididymis (cellular debris), seminal vesicle/prostate (atrophy), and testis (weights, tubular degeneration). These findings were observed at the lowest tested dose of 5 mg/kg/day in the 13-week rat study, resulting in an exposure level 26-fold higher than the human exposure at 50 mg daily dose.
Vorasidenib caused embryo-foetal toxicity in pregnant rats and rabbits (higher incidence of resorptions, delayed ossification, visceral malformations for kidney and testes in rats). These effects occurred at doses that were higher compared to patients receiving the therapeutic daily dose. The exposure ratios at the NOAEL for embryo-foetal development in rats and rabbits were 8.0 to 28.5 and 1.1 to 4.9, respectively, on gestation days 6 and 17 for rat and 6 and 19 for rabbit.
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