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.