Chemical formula: C₂₈H₂₂ClF₃N₆O₃ Molecular mass: 582.97 g/mol
Ivosidenib is an inhibitor of the mutant IDH1 enzyme. Mutant IDH1 converts alpha- ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG) which blocks cellular differentiation and promotes tumorigenesis in both hematologic and non-hematologic malignancies. The mechanism of action of ivosidenib beyond its ability to reduce 2-HG and restore cellular differentiation is not fully understood across indications.
Multiple doses of ivosidenib 500 mg daily decreased plasma concentrations of 2-HG in patients with hematological malignancies and cholangiocarcinoma with mutated IDH1 to levels approximating those observed in healthy subjects. In bone marrow of patients with hematological malignancies and in tumour biopsy of patients with cholangiocarcinoma, the mean (% coefficient of variation [CV]) reduction in 2-HG concentrations were 93.1 (11.1%) and 82.2% (32.4%), respectively.
Using an ivosidenib concentration-QTc model, a concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.7, 19.7) was predicted at the steady-state Cmax based on an analysis of 173 patients with AML who received 500 mg ivosidenib once daily. A concentrationdependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.3, 20.2) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 101 patients with cholangiocarcinoma who received ivosidenib 500 mg daily.
A total of 10 clinical studies have contributed to the characterisation of the clinical pharmacology of ivosidenib. Five studies have been conducted in healthy subjects and 3 studies have been conducted in patients with advanced malignancies including 2 studies in patients with cholangiocarcinoma. Two studies have been conducted in patients with newly diagnosed AML receiving ivosidenib in combination with azacitidine. Pharmacokinetic endpoints have been assessed in plasma and urine. Pharmacodynamic endpoints have been assessed in plasma, urine, tumour biopsy, and bone marrow (for studies in patients with advanced malignancies only).
The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML and cholangiocarcinoma.
After a single 500 mg oral dose, the median time to Cmax (Tmax) was approximately 2 hours in newly diagnosed AML patients treated with a combination of ivosidenib and azacitidine and in cholangiocarcinoma patients.
In patients with newly diagnosed AML treated with a combination of ivosidenib (500 mg daily dose) and azacitidine, the mean steady-state Cmax was 6,145 ng/mL (CV%: 34) and the mean steady-state AUC was 106,326 ng hr/mL (CV%: 41).
In patients with cholangiocarcinoma, the mean Cmax was 4,060 ng/mL (CV: 45) after a single dose of 500 mg and 4,799 ng/mL (CV: 33) at steady state for 500 mg daily. The AUC was 86,382 ng·hr/mL (CV%: 34).
Accumulation ratios were approximately 1.6 for AUC and 1.2 for Cmax in patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine and approximately 1.5 for AUC and 1.2 for Cmax in patients with cholangiocarcinoma, over one month, when ivosidenib was administered at 500 mg daily. Steady-state plasma levels were reached within 14 days of once daily dosing.
Significant increases in ivosidenib Cmax (by approximately 98%; 90% CI: 79, 119) and AUCinf (by approximately 25%) were observed following administration of a single dose with a high-fat meal (approximately 900 to 1,000 calories, 56% to 60% fat) in healthy subjects.
Based on a population pharmacokinetic analysis the mean apparent volume of distribution of ivosidenib at steady-state (Vc/F) is 3.20 L/kg (CV%: 47.8) in patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine and 2.97 L/kg (CV%: 25.9) in patients with cholangiocarcinoma treated with ivosidenib monotherapy.
Ivosidenib was the predominant component (>92%) of total radioactivity in plasma from healthy subjects. It is primarily metabolised by oxidative pathways mediated largely by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.
Ivosidenib induces CYP3A4 (including its own metabolism), CYP2B6, CYP2C8, CYP2C9, and may induce CYP2C19 and UGTs. Therefore, it may decrease systemic exposure to substrates of these enzymes.
Ivosidenib inhibits P-gp in vitro and has the potential to induce P-gp. Therefore, it may alter systemic exposure to active substances that are predominantly transported by P-gp.
In vitro data suggest that ivosidenib has the potential to inhibit OAT3, OATP1B1 and OATP1B3 at clinically relevant concentrations and it may, therefore, increase systemic exposure to OAT3, OATP1B1 or OATP1B3 substrates.
In patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine, the mean apparent clearance of ivosidenib at steady state was 4.6 L/hour (35%) with a mean terminal halflife of 98 hours (42%).
In patients with cholangiocarcinoma, the mean apparent clearance of ivosidenib at steady state was 6.1 L/hour (31%) with a mean terminal half-life of 129 hours (102%).
In healthy subjects, 77% of a single ivosidenib oral dose was found in the faeces of which 67% was recovered unchanged. Approximately 17% of a single oral dose was found in the urine of which 10% was recovered unchanged.
The AUC and Cmax of ivosidenib increased in a less than dose proportional manner from 200 mg to 1,200 mg once daily (0.4 to 2.4 times the recommended dose).
No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in older patients up to 84 years. The pharmacokinetics of ivosidenib in patients 85 years of age or older is unknown.
No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or renal impairment requiring dialysis are unknown.
Using the NCI classification, no clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in patients with mild hepatic impairment. The pharmacokinetics of ivosidenib in patients with moderate and severe hepatic impairment are unknown in patients with newly diagnosed AML and with cholangiocarcinoma. No PK data in patients with hepatic impairment stratified by the Child-Pugh classification are available.
No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on gender, race, body weight or ECOG performance status.
The potential of ivosidenib for QT prolongation was evidenced in in vitro and in vivo preclinical studies at clinically relevant plasma levels.
In animal studies at clinically relevant exposures, ivosidenib induced haematologic abnormalities (bone marrow hypocellularity, lymphoid depletion, decreased red cell mass together with extramedullary haematopoiesis in the spleen), gastrointestinal toxicity, thyroid findings (follicular cell hypertrophy/hyperplasia in rats), liver toxicity (elevated transaminases, increased weights, hepatocellular hypertrophy and necrosis in rats and hepatocellular hypertrophy associated with increased liver weights in monkeys) and kidney findings (tubular vacuolation and necrosis in rats). Toxic effects observed on haematologic system, GI system and kidney were reversible whereas the toxic effects observed on liver, spleen and thyroid were still observed at the end of the recovery period.
Ivosidenib was not mutagenic or clastogenic in conventional in vitro and in vivo genotoxicity assays. Carcinogenicity studies have not been conducted with ivosidenib.
Fertility studies have not been conducted with ivosidenib. In the 28-day repeat dose toxicity study in rats, uterine atrophy was observed in females at non-tolerated dose levels approximately 1.7-fold the clinical exposure (based on AUC) and was reversible after a 14-day recovery period. Testicular degeneration was observed in males at non-tolerated dose levels approximately 1.2-fold the clinical exposure (based on AUC) in animals prematurely euthanized.
In embryofoetal development studies in rats, lower foetal body weights and delayed skeletal ossification occurred in the absence of maternal toxicity. In rabbits, maternal toxicity, spontaneous abortions, decreased foetal body weights, increased post implantation loss, delayed skeletal ossification and visceral development variation (small spleen) were observed. Animal studies indicate that ivosidenib crosses the placenta and is found in foetal plasma. In rats and rabbits, the no adverse effect levels for embryofoetal development were 0.4-fold and 1.4-fold the clinical exposure (based on AUC), respectively.
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