Effect of itraconazole, food, and ethnic origin on the pharmacokinetics of ivosidenib in healthy subjects

Abstract

Purpose To assess the effect of ethnicity, food, and itraconazole (strong CYP3A4 inhibitor) on the pharmacokinetics of ivosidenib after single oral doses in healthy subjects. Methods Three 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). Results Ivosidenib was well tolerated in all three studies. Study 1: pharmacokinetic profiles were generally comparable, although AUC and C max were slightly lower in Japanese subjects than in Caucasian subjects, by~30 and 17%, respectively. Study 2: AUC increased by~25% and C max 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 C max . Conclusions No 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.

Population pharmacokinetic and exposure‐response analyses of ivosidenib in patients with IDH1‐mutant advanced hematologic malignancies

“…10 The covariate effects of moderate and strong CYP3A4 inhibition with concomitant voriconazole, fluconazole, and posaconazole had a moderate effect on ivosidenib exposure based on AUC. Although the detailed dose, regimen, and compliance for these concomitant medications were unknown in this study, the magnitude of strong CYP3A4 inhibition predicted from this analysis was broadly similar to the results from a dedicated clinical pharmacology study of the effect of the strong CYP3A4 inhibitor itraconazole on ivosidenib exposure (1.69-fold change in plasma AUC in healthy participants after multiple doses of ivosidenib) 15 and a physiologically based PK model prediction (1.44-fold change in plasma AUC in patients with AML after multiple doses of ivosidenib in the presence of itraconazole). 12 Thus, co-administration of strong CYP3A4 inhibitors with ivosidenib requires an ivosidenib dose reduction.…”

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants

“…Ivosidenib has a moderate food effect on C max , which is attributed to its solubility‐limited absorption 3 . Participants with hepatic impairment may have changes in gastrointestinal environment, such as bile salt content and phospholipids, which influence the solubility of the drug and thus reduce ivosidenib absorption.…”

“…Several clinical studies to date have shown that ivosidenib is readily absorbed and slowly eliminated after a single dose in healthy participants and in patients with advanced mutant IDH1 solid and hematologic malignancies 1,3,4 . In vitro and in vivo studies identified the liver as a primary organ involved in the clearance of ivosidenib.…”

“…Since no circulating metabolites were observed in plasma, the pharmacological activity of metabolites was not evaluated or characterized in that or the current study. In a clinical drug‐drug interaction study, a noteworthy interaction was observed when ivosidenib was coadministered with itraconazole, a strong CYP3A4 inhibitor 3 . The area under the plasma concentration–time curve (AUC) and terminal elimination half‐life (t ½ ) of ivosidenib increased by 2.6‐ and 2.3‐fold, respectively, indicating that hepatic metabolism via CYP3A4 is a major metabolic pathway for in vivo elimination of ivosidenib.…”

Evaluating ivosidenib for the treatment of acute myeloid leukemia

“…A steady state was achieved within 14 days of administration. A single-dose food effect study in healthy subjects indicated that a high-fat meal increased the mean peak plasma concentration by 98% [47]. Therefore, it is advised that ivosidenib should not be administered with a high fat meal.…”