PURPOSE: Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). METHODS: Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. RESULTS: Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib. CONCLUSIONS: Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02074839.
PURPOSE: Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). METHODS: Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. RESULTS: Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib. CONCLUSIONS: Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02074839.
Authors: Bin Fan; Yue Chen; Feng Yin; Lei Hua; Caroline Almon; Salah Nabhan; Michael Cooper; Hua Yang; Mohammad Hossain Journal: Clin Pharmacol Drug Dev Date: 2022-02-14
Authors: Courtney D DiNardo; Anthony S Stein; Eytan M Stein; Amir T Fathi; Olga Frankfurt; Andre C Schuh; Hartmut Döhner; Giovanni Martinelli; Prapti A Patel; Emmanuel Raffoux; Peter Tan; Amer M Zeidan; Stéphane de Botton; Hagop M Kantarjian; Richard M Stone; Mark G Frattini; Frederik Lersch; Jing Gong; Diego A Gianolio; Vickie Zhang; Aleksandra Franovic; Bin Fan; Meredith Goldwasser; Scott Daigle; Sung Choe; Bin Wu; Thomas Winkler; Paresh Vyas Journal: J Clin Oncol Date: 2020-10-29 Impact factor: 44.544
Authors: Eytan M Stein; Courtney D DiNardo; Amir T Fathi; Alice S Mims; Keith W Pratz; Michael R Savona; Anthony S Stein; Richard M Stone; Eric S Winer; Christopher S Seet; Hartmut Döhner; Daniel A Pollyea; James K McCloskey; Olatoyosi Odenike; Bob Löwenberg; Gert J Ossenkoppele; Prapti A Patel; Mikhail Roshal; Mark G Frattini; Frederik Lersch; Aleksandra Franovic; Salah Nabhan; Bin Fan; Sung Choe; Hongfang Wang; Bin Wu; Lei Hua; Caroline Almon; Michael Cooper; Hagop M Kantarjian; Martin S Tallman Journal: Blood Date: 2021-04-01 Impact factor: 22.113