Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors

Abstract

Background 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 Registration ClinicalTrials.gov (NCT02073994).

Second‐line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes

“…[14][15][16] Some of these molecular subtypes, including tumors harboring FGFR2 fusions, IDH1 mutations, HER2 amplification, or mismatch repair deficiency, may be amenable to molecularly targeted therapies or immunotherapy according to promising evidence in case series and early-phase clinical trials. [17][18][19][20][21][22][23][24] Notably, however, this retrospective analysis preceded the activation of clinical trials of targeted inhibitors of FGFR2, mutant IDH1, or mismatch repair deficiency for cholangiocarcinoma at the study sites; thus, the efficacy of targeted inhibitors in these contexts is not likely to have contributed to the more favorable outcomes for the intrahepatic subgroup of this study. Extrahepatic cholangiocarcinomas are associated with an increased risk for biliary obstruction, which can limit treatment options and lead to competing comorbidities such as cholangitis and sepsis, factors that are likely to have contributed to the poorer outcomes observed in the extrahepatic subgroup of this study and that underscore the importance of multidisciplinary supportive care in this population.…”

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…122 A total of 168 patients with IDH1-mutated cholangiocarcinoma and chondrosarcoma were treated to explore pharmacokinetic and pharmacodynamic profiles. 123 Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40-102 hours after a single dose). Steady state was reached by day 15, and its metabolism was not affected by any of the intrinsic or extrinsic factors assessed (including weak CYP3A4 inhibitors/inducers).…”

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

“…The phase 1 data of ivosidenib showed rapid oral absorption and a long half-life of 40 to 102 h after one single administration of the drug [75]. Ivosidenib had an acceptable tolerability profile, with only few dose reductions or discontinuations due to toxicities noted in the phase 1 trial; the most frequent side effects encountered in the AML population were diarrhoea, leucocytosis, febrile neutropenia, nausea, fatigue, QT prolongation, pyrexia and anaemia [77].…”

“…Ivosidenib (previously known as AG-120), is a first-inclass selective oral IDH1 inhibitor that targets the mutant IDH1 protein and was developed by Agios Pharmaceuticals. It showed clinical activity in a phase 1, open-label, multicentre study with 168 patients with advanced solid tumours (NCT02073994) [74,75]. Enasidenib, also known as AG-221, another IDH inhibitor developed by Agios Pharmaceuticals, is a first-in-class orally potent selective IDH2 inhibitor, targeting the mutant IDH2 enzymes [76].…”