Abstract
SummaryBackground Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).
Highlights
Isocitrate dehydrogenase (IDH) is a critical metabolic enzyme, catalyzing the oxidative decarboxylation of isocitrate to pro-Erika Manyak, Sam Agresta, and David Dai Affiliation at time of study Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the article duce carbon dioxide and alpha-ketoglutarate (α-KG)
Mutations in the IDH1 and IDH2 genes are found in multiple hematologic and solid tumors, including acute myeloid leukemia (AML) and glioma
We report the pharmacokinetic (PK) and pharmacodynamic (PD) data associated with ivosidenib treatment in these patients, and the effects of intrinsic and extrinsic factors on ivosidenib clearance
Summary
Isocitrate dehydrogenase (IDH) is a critical metabolic enzyme, catalyzing the oxidative decarboxylation of isocitrate to pro-. Extended author information available on the last page of the article duce carbon dioxide and alpha-ketoglutarate (α-KG). Mutant IDH enzymes are not catalytically inactive, but rather possess a novel enzymatic activity, catalyzing the reduction of α-KG to the oncometabolite D-2hydroxyglutarate (2-HG) [1, 2]. In cells with IDH1/IDH2 mutant enzymes, the accumulation of 2-HG alters a number of downstream cellular activities, causing epigenetic dysregulation and a block in cellular differentiation, leading to tumorigenesis [3,4,5]
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