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

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 (C(max)) was 525 (66) ng/mL, at median time to maximum concentration (t(max)) of 2 hours. Mean (coefficient of variation) area under the plasma concentration–time curve from time 0 to time t (AUC(0‐t)) was 3392 (63.3) ng • h/mL, and arithmetic mean terminal half‐life was 18.6 hours. Acyl glucuronide metabolite (M1)/navtemadlin AUC(0‐t) ratio was 0.2, and urine excretion of navtemadlin was negligible. After a meal (B vs A), navtemadlin t(max) was delayed by 1 hour. Geometric least squares means ratios (90%CI) for navtemadlin C(max) and AUC(0‐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 C(max) and 85.9% (80.5‐91.7) for AUC(0‐t). MIC‐1 C(max) and AUC were comparable across groups; t(max) was delayed relative to navtemadlin t(max) by ≈8 hours. Navtemadlin AUC(0‐t) and MIC‐1 AUC(0‐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.