• David Dai, Hua Yang, Salah Nabhan, Hua Liu, Denice Hickman, Guowen Liu, Jeffrey Zacher, Apinya Vutikullird, Chandra Prakash, Samuel Agresta, Chris Bowden, and Bin Fan.
• Agios Pharmaceuticals, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA.
• Eur. J. Clin. Pharmacol. 2019 Aug 1; 75 (8): 1099-1108.

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.GOV : NCT03071770, NCT02579707, and NCT02831972.

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