No abstract

Objective: FCN-159 is a highly active mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor in patients with advanced melanoma and neurofibromatosis type 1 (NF1). We report a population pharmacokinetic (PopPK) model-based analysis of FCN-159 and its application to inform dose selection for NF1 pediatric trials.Methods: PK data collected from patients with advanced melanoma and NF1 in two clinical studies (NCT03932253 and NCT04954001) were analyzed using a non-linear mixed effects model. The adult model was adapted by incorporating allometric scaling for PK projection in 2–17 years old children. Pediatric exposure in different body surface area (BSA) bins was simulated to identify nominal doses (i.e., dose amounts given as integers) and BSA bin cutoffs to achieve exposure comparable to adults’ optimal exposure across the entire pediatric BSA range.Results: The final dataset consisted of 45 subjects with a total of 1030 PK samples. The PK of FCN-159 was well-described by a 2-compartment model with first-order linear elimination and delayed first-order absorption. Covariates, including BSA, age, sex, albumin, total protein, and cancer type, were identified as statistically significant predictors of FCN-159 disposition. Simulations based on the final model projected daily doses of 4 mg/m2 QD with optimized BSA bin cutoffs would allow fixed nominal doses within each bin and result in steady state exposure approximating the adult exposure observed at the recommended phase 2 dose (RP2D) in NF1, which is 8 mg QD.Conclusion: The developed population PK model adequately described the PK profile of FCN-159, which was adapted using allometric scaling to inform dose selection for NF1 pediatric trials.

Meal timings and content related to gallbladder emptying in the enterohepatic circulation are important for explaining the high variability in mycophenolic acid exposure. The limited sampling strategy (LSS) was established to estimate the area under the plasma concentration–time curve from time 0 to 12 hours (AUC0‐12h) of mycophenolic acid in therapeutic drug monitoring. The aim of this study is to investigate the effect of meal timings and content on the AUC0‐12h of mycophenolic acid and to assess the influence of meals on LSS. A mycophenolic acid pharmacokinetic model with a mechanism‐based enterohepatic circulation process was employed to perform simulations under various assumed meal scenarios. The simulations were compared to evaluate the effect of meal timings and meal content on mycophenolic acid AUC0‐12h. Monte Carlo simulations were performed using the meal parameter with the greatest impact on mycophenolic acid AUC0‐12h as a variable. The corresponding LSS equations were established, and the predictive performance was assessed. Both the meal timings and meal content affected the mycophenolic acid AUC0‐12h, and the postdose fasting period had the greatest impact. The predictive performance of the LSS is sensitive to the postdose fasting period. Therefore, meal timings may improve the estimation of mycophenolic acid AUC0‐12h and the efficacy of therapeutic drug monitoring.