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

Abstract

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure-response (efficacy [n = 201] and safety [n = 253]), and concentration-corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300-1200 mg q.d.). Ivosidenib disposition was well-described by a two-compartment PK model with first-order absorption and elimination. Between-subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration-time curve at steady state (AUCss ) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss , there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration-QT analysis showed a mean change in QTc using Fridericia's method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model-based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure-response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.

Trial registration: ClinicalTrials.gov NCT02074839.

Conflict of interest statement

X.J., G.L., H.L., and S.K. are employees and stockholders of Agios Pharmaceuticals, Inc. R.W., B.P., and H.J.K. are employees of Certara and contracted to perform research for Agios Pharmaceuticals, Inc. B.F., H.Y., and K.L. were employees and stockholders of Agios Pharmaceuticals, Inc. when the work was carried out.

© 2020 Agios Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

(a) Schematic of final population pharmacokinetic model and (b) visual predictive check. In (b), the blue shaded regions represent 90% prediction intervals on the range of prediction‐corrected data. The red solid lines represent the simulated 5th, 50th, and 95th percentiles for 1000 simulations, and the blue dashed lines represent corresponding statistics for the prediction‐corrected observed data. The right panel includes all samples after day –3 in patients in the dose escalation phase and cycle 1 day 1 in patients in the dose expansion phase. The x‐axis represents time after dose, and predose samples are plotted at ~ 24 h. CL, clearance; Frel, relative bioavailability on day 1; Ka, first‐order absorption rate constant; Q, between‐compartment clearance; Tlag, zero‐order release duration (lag‐time); SS, steady state; Vc, volume of distribution for central compartment; Vp, volume of distribution for the peripheral compartment

FIGURE 2

Forest plot of covariates and dose for (a) area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) and (b) maximal plasma ivosidenib concentration (Cmax); and (c) factors explaining variability in AUCss estimates. In (a) and (b), the vertical lines represent the predicted AUCss (93 µg·h/ml) and Cmax (4827 ng/ml) in the typical patient receiving ivosidenib 500 mg once daily (q.d.). This patient has albumin levels of 37 g/L and is not taking a strong or moderate concomitant CYP3A4 inhibitor. The top hatched bar shows the 5th to 95th percentiles of modeled AUCss and Cmax, across the patient population. The points show the variation in modeled AUC and Cmax as covariates are changed one at a time to indicated values. For continuous variables, the extreme values are 5th and 95th percentiles of the population. Horizontal lines represent 95th percentile confidence intervals of the estimate. Albumin ratio calculated as albumin at a given time divided by baseline albumin (reflects within‐patient variability)

FIGURE 3

(a) Exposure versus adverse event (AE) occurrence, with vertical boxplots showing area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) distributions for each AE and (b) post hoc AUCss distributions in responders and nonresponders for efficacy end points overall response, complete remission, complete remission or complete remission with partial hematologic recovery (CR/CRh), and non‐CR/CRh response. Dots represent the median; hinges represent the 25th and 75th percentiles; and whiskers represent extended hinges to 1.5 × interquartile range. Not shown: ≥grade 3 polyneuropathy and liver dysfunction, both n = 1. ARF, acute renal failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IDH, isocitrate dehydrogenase

FIGURE 4

Adverse event (AE) incidence versus area under the plasma ivosidenib concentration‐time curve at steady state (AUCss) with incidence grouped by AUCss quartile and a linear logistic regression fit for alanine aminotransferase (ALT) or aspartate aminotransferase (AST) AEs. Numbers represent total number of subjects (upper row) and number of subjects with an event (lower row) within corresponding quartile; solid dot and vertical line represent incidence and 95% confidence interval (CI) of observation within quartile; bold solid line is the logistic regression fit of the form: Response ~AUCss * slope + intercept; dashed lines are the 95% CI; horizontal solid lines are the width of exposure quartiles. ALT, alanine aminotransferase; AST, aspartate aminotransferase

FIGURE 5

Relationship between mean change in corrected QT interval using Fridericia's method (∆QTcF) and ivosidenib concentration. CI, confidence interval