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

Taylor, Adekemi; Lee, Dana; Allard, M.; Poland, Bill; Slatter, J. Greg

doi:10.1002/cpdd.903

Cited by 12 publications

(10 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 ].…”

Section: Gut Flora Modifying Agentsmentioning

confidence: 99%

Evidence-based approach to management of hepatic encephalopathy in adults

Hoilat¹,

Suhail²,

Adhami³

et al. 2022

WJH

View full text Add to dashboard Cite

Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function and represents one of the many complications of portal hypertension and decompensated liver disease. Although ammonia is clearly implicated in the pathogenesis of HE, the pathogenesis of HE is multifactorial with numerous mechanisms that results in functional impairment of neuronal cells. The initial management of HE focuses on supportive care and stabilization which includes providing appropriate nutritional support. Thereafter, focus should be on identifying and treating the precipitating factors. There are many therapeutic agents available for the management of HE, most of which are directed towards lowering the gut nitrogen load and thus the serum ammonia level. This review aims to provide an update on the conventional and emerging treatment options for HE.

show abstract

Section: Gut Flora Modifying Agentsmentioning

confidence: 99%

Evidence-based approach to management of hepatic encephalopathy in adults

Hoilat¹,

Suhail²,

Adhami³

et al. 2022

WJH

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Navtemadlin (Previously Krt232 and Amg232mentioning

confidence: 99%

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

Kagan

Anders

Hemingway

et al. 2022

Biomedical Chromatography

View full text Add to dashboard Cite

Navtemadlin is an orally bioavailable small molecule that blocks the protein-protein interaction between murine double minute 2 protein (MDM2) and the tumor suppressor protein p53, leading to p53-mediated cell cycle arrest and apoptosis. It is being evaluated in clinical trials for a variety of malignancies, both as a single agent and in combination regimens. A sensitive, robust LC-tandem mass spectrometry (LC-MS/MS) method was developed to quantitate navtemadlin in plasma, and this method was also validated using brain tissue homogenate. Sample preparation involved protein precipitation of plasma or brain tissue homogenate using acetonitrile. Navtemadlin, navtemadlin glucuronide, and the internal standard, D 6 -navtemadlin, were separated from microsomal incubation extracts using gradient elution and a ZORBAX XDB C 18 column. Analytes were detected using a SCIEX 5500 triple quadrupole mass spectrometer in positive electrospray ionization mode. The assay range of 1-1000 ng/mL was shown to be accurate (96.1-102.0% and 95.7-104%) and precise (coefficient of variation ≤ 10.6% and ≤ 6.6%) in plasma and brain tissue homogenate, respectively. An 8000 ng/mL navtemadlin sample diluted 1:10 (v/v) with plasma was also accurately quantitated. Navtemadlin has been stable in frozen plasma at À70 C for at least 20 months. This validated LC-MS/MS method was applied to determine navtemadlin concentrations in plasma and brain tissue samples from two separate patients receiving 120 mg/day navtemadlin on protocol ABTC1604.

show abstract

“…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 .…”

mentioning

confidence: 99%

“… 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.…”

mentioning

confidence: 99%

“… 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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Wong

Krejsa

Lee

et al. 2022

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

This single 60‐mg dose, 4‐period crossover study assessed the effect of food and formulation change on navtemadlin (KRT‐232) pharmacokinetics (PK) and macrophage inhibitory cytokine‐1 (MIC‐1) pharmacodynamics. Healthy subjects (N = 30) were randomized to 3 treatment sequences, A: new tablet, fasted (reference, dosed twice); B: new tablet, 30 minutes after a high‐fat meal (test 1); C: old tablet, fasted (test 2). PK/pharmacodynamic parameters were measured over 0 to 96 hours. Adverse events were mild without any discontinuations. No serious adverse events or deaths occurred. In treatment A, navtemadlin mean (coefficient of variation) maximum concentration (Cmax) was 525 (66) ng/mL, at median time to maximum concentration (tmax) of 2 hours. Mean (coefficient of variation) area under the plasma concentration–time curve from time 0 to time t (AUC0‐t) was 3392 (63.3) ng • h/mL, and arithmetic mean terminal half‐life was 18.6 hours. Acyl glucuronide metabolite (M1)/navtemadlin AUC0‐t ratio was 0.2, and urine excretion of navtemadlin was negligible. After a meal (B vs A), navtemadlin tmax was delayed by 1 hour. Geometric least squares means ratios (90%CI) for navtemadlin Cmax and AUC0‐t were 102.7% (87.4‐120.6) and 81.4% (76.2‐86.9), respectively. Old vs new tablet fasted formulations (C vs A) had geometric least squares means ratios (90%CI) of 78.4% (72.0‐85.3) for Cmax and 85.9% (80.5‐91.7) for AUC0‐t. MIC‐1 Cmax and AUC were comparable across groups; tmax was delayed relative to navtemadlin tmax by ≈8 hours. Navtemadlin AUC0‐t and MIC‐1 AUC0‐t correlated significantly. In conclusion, navtemadlin can be administered safely with or without food; the new formulation does not affect navtemadlin PK. The 60‐mg navtemadlin dose elicited a reproducible and robust MIC‐1 response that correlated well with navtemadlin exposure, indicating that murine double minute 2 target engagement leads to p53 activation.

show abstract

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

Cited by 12 publications

References 17 publications

Evidence-based approach to management of hepatic encephalopathy in adults

Evidence-based approach to management of hepatic encephalopathy in adults

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

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

Contact Info

Product

Resources

About