Phase 1 Concentration‐QTc and Cardiac Safety Analysis of the MDM2 Antagonist KRT‐232 in Patients With Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Abstract

Cardiac safety and plasma concentration-QTc interval analyses were completed using data from 2 phase 1 studies of the selective mouse double minute chromosome 2 antagonist, KRT-232, in patients with solid tumors or multiple myeloma and acute myeloid leukemia (AML) who received KRT-232 doses of 15 to 480 mg once daily (QD; N = 130). A linear mixed-effects model related change from baseline Fridericia-corrected QT interval (QTcF) to KRT-232 plasma concentrations. The final model included parameters for the intercept (with between-subject variability),KRT-232 concentration-QTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. Mean (90% confidence interval) predicted QTcF values at the maximum clinical dose (480 mg QD) were 2.04 (0.49-3.60) milliseconds for patients with solid tumors and 4.52 (2.35-6.69) milliseconds for patients with AML. Because the 90% confidence interval upper bound of the mean QTcF was predicted to be below 10 milliseconds at doses up to 480 mg QD in patients with solid tumors, multiple myeloma, or AML, KRT-232 does not result in clinically meaningful QT prolongation at the doses currently under investigation in clinical trials. No significant cardiac safety concerns were identified at these doses.

Evidence-based approach to management of hepatic encephalopathy in adults

“…Another study[ 30 ] showed that 2/10 patients required hospitalization and 3/10 developed an encephalopathy episode after FMT at 20 wk. FMT also appeared to be safe and well tolerated[ 31 ].…”

Quantitation of navtemadlin in human plasma and brain tissue by liquid chromatography–tandem mass spectrometry

“…Navtemadlin is now being evaluated in the treatment of a variety of malignancies, including leukemia, myeloproliferative neoplasms, myeloma, sarcoma, lung cancer, and brain cancer, both as a single agent and as a part of combination regimens. Erba et al (2019) previously reported an LC-tandem mass spectrometry (LC-MS/MS) bioanalytical method for the pharmacokinetic analysis of navtemadlin in NCT02016729; this method has subsequently been used in other clinical studies (Gluck et al, 2020;Taylor et al, 2021). However, these prior studies lack sufficient details of the bioanalytical method, including but not limited to sample preparation, chromatography, and stability information, and they have also not validated the method using brain tissue.…”

Pharmacokinetics and Macrophage Inhibitory Cytokine‐1 Pharmacodynamics of the Murine Double Minute 2 Inhibitor, Navtemadlin (KRT‐232) in Fed and Fasted Healthy Subjects

“…Navtemadlin is a small‐molecule, highly protein‐bound (97.5%) monoprotic carboxylic acid (pK a 4.35) that is primarily metabolized to a major circulating acyl glucuronide metabolite (M1) 17 . The structure of navtemadlin and M1 have been previously published 17–19 . In previous studies, M1 has been shown to be stable in vitro and demonstrated 5‐fold less pharmacologic activity than the parent drug in a biochemical homogeneous time‐resolved fluorescence in vitro pharmacologic potency assay in the presence of 15% serum and was highly bound to plasma proteins 19 .…”

“… 17 The structure of navtemadlin and M1 have been previously published. 17 , 18 , 19 In previous studies, M1 has been shown to be stable in vitro and demonstrated 5‐fold less pharmacologic activity than the parent drug in a biochemical homogeneous time‐resolved fluorescence in vitro pharmacologic potency assay in the presence of 15% serum and was highly bound to plasma proteins. 19 In patients with solid tumors or multiple myeloma, the mean time to maximum concentration (t max ) of the metabolite M1 was 2 to 4‐hours, and the mean (standard deviation [SD]) terminal half‐life (t 1/2 ) was 14.0 (6.07) hours.…”

“… 17 , 18 , 19 In previous studies, M1 has been shown to be stable in vitro and demonstrated 5‐fold less pharmacologic activity than the parent drug in a biochemical homogeneous time‐resolved fluorescence in vitro pharmacologic potency assay in the presence of 15% serum and was highly bound to plasma proteins. 19 In patients with solid tumors or multiple myeloma, the mean time to maximum concentration (t max ) of the metabolite M1 was 2 to 4‐hours, and the mean (standard deviation [SD]) terminal half‐life (t 1/2 ) was 14.0 (6.07) hours. The mean accumulation for metabolite M1 over a 7‐day once‐daily dosing period was <2‐fold, and the mean metabolite‐to‐parent 24‐hour area under the plasma concentration–time curve (AUC) ratio was 0.461.…”