Abstract
PurposeTo assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects.MethodsThree phase 1 open-label studies were performed. Study 1: Japanese and Caucasian subjects received single doses of 250, 500, or 1000 mg ivosidenib (NCT03071770). Part 1 of study 2 (a two-period crossover study): subjects received 500 mg ivosidenib after either an overnight fast or a high-fat meal. Subjects received 1000 mg ivosidenib after an overnight fast in the single period of part 2 (NCT02579707). Study 3: in period 1, subjects received 250 mg ivosidenib; then, in period 2, subjects received oral itraconazole (200 mg once daily) on days 1–18, plus 250 mg ivosidenib on day 5 (NCT02831972).ResultsIvosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and Cmax were slightly lower in Japanese subjects than in Caucasian subjects, by ~ 30 and 17%, respectively. Study 2: AUC increased by ~ 25% and Cmax by ~ 98%, when ivosidenib was administered with a high-fat meal compared with a fasted state. Study 3: co-administration of itraconazole increased ivosidenib AUC by 169% (90% CI 145–195) but had no effect on ivosidenib Cmax.ConclusionsNo ivosidenib dose adjustment is deemed necessary for Japanese subjects. High-fat meals should be avoided when ivosidenib is taken with food. When co-administered with strong CYP3A4 inhibitors, monitoring for QT interval prolongation (a previously defined adverse event of interest) is recommended and an ivosidenib dose interruption or reduction may be considered.ClinicalTrials.govNCT03071770, NCT02579707, and NCT02831972.
Highlights
Somatic mutations in isocitrate dehydrogenase (IDH) 1 and 2 confer a gain of function, modifying the activity of the enzymeElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.USA so that it catalyzes the reduction of alpha-ketoglutarate to the oncometabolite D(-)2-hydroxyglutarate (2-HG) [1, 2]. 2-HG exerts its oncogenic effects via several pathways, including the competitive inhibition of α-KG-dependent dioxygenases that modulate gene expression [3, 4], blocking normal cellular differentiation [5]
It is estimated that 6–10% of patients with acute myeloid leukemia (AML) carry IDH1 mutations [2, 8,9,10]
In vitro studies have shown that ivosidenib is predominantly metabolized by CYP3A4 [16, 18]. These findings indicate that coadministration of CYP3A4 inhibitors has the potential to increase ivosidenib exposure and thereby increase the risk of toxicity
Summary
2-HG exerts its oncogenic effects via several pathways, including the competitive inhibition of α-KG-dependent dioxygenases that modulate gene expression [3, 4], blocking normal cellular differentiation [5]. Direct inhibition of mutant IDH1 (mIDH1) suppresses the production of 2-HG, restoring cellular differentiation [6]. Cancer-associated mutations in IDH1 and IDH2 have been identified in a range of hematologic malignancies and solid tumors [7]. It is estimated that 6–10% of patients with acute myeloid leukemia (AML) carry IDH1 mutations [2, 8,9,10]. Metaanalyses evaluating the prognostic impact of mIDH1 in patients with AML suggest that mIDH1 is associated with worse outcomes compared with wild-type IDH1 [11,12,13]. The prognosis of patients with relapsed/refractory (R/R) AML is especially poor and treatment options are inadequate [14]
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