Associate Director, Pharmacometrics Allucent, LLC, United States
Disclosure(s):
James Clary: No financial relationships to disclose
Objectives: SAT-3247 is being developed for the treatment of Duchenne Muscular Dystrophy (DMD). Healthy adult volunteers received SAT-3247 and their pharmacokinetic data were used to extrapolate to pediatric patients. A population PK (popPK) model was developed and extrapolated to pediatric patients. Simulations were performed to help inform dosing for potential pediatric trials in various age ranges (age 4-6 years, 7-9 years, 10-12 years) with daily dosing for 5 days followed by 2 days off (12 cycles). The goal was to maximize the number of individuals in each potential age range achieving time above the target IC50 (130 ng/mL) ≥ 6 hours.
Methods: A popPK model was developed in adults (Monolix 2024R1) and allometrically scaled to pediatric patients. Ages and weights for pediatric patients were drawn for male individuals from the NHANES[1] dataset for the 3 cohorts (R 4.0.3). One-hundred trial simulations were performed with uncertainty in the parameter estimates (Simulx 2024R1) drawing 20 individuals per cohort without replacement within a trial. Two simulations were run: 1) proposed doses of 60 and 120 mg flat doses versus 1, 1.5, and 2 mg/kg dosing. 2) proposed doses of 60 and 120 mg versus 50 and 100 mg doses (chosen to reduce pill burden). All dosing paradigms were simulated as 5 days on 2 days off for 12 weeks.
Results: The final adult popPK model was 3-compartment model with zero-order absorption Michaelis Menten clearance. Dose level was parameterized as an Emax model on bioavailability, with both food and sex effects on absorption. All parameter estimates had reasonable precision with a relative standard error below 45%.
For the first set of simulations, a dose of 2.0 mg/kg for ages 4-6 years (median: 30.6 mg) and 1.5 mg/kg for ages 7-12 years (median: 45.2 and 70.1 mg, respectively) is sufficient to achieve time above the IC50 ≥ 6 hours at first dose. Similarly, 60 and 120 mg achieve time above the IC50 ≥ 6 hours at first dose.
For the second set of simulations, additional doses of 50 mg for the age 4-6 cohort and 100 mg for the age 7-9 and 10-12 cohorts were assessed to reduce pill burden. For the first cohort, a 50 mg dose achieved a median time above the IC50 of 10.7 hours, and a 60 mg dose achieved a median time above the IC50 of 13.1 hours. For the older cohorts, a 60 mg dose achieved a median time above the IC50 of 9.8 and 7.1 hours, respectively, and a 100 mg dose achieved a median time above the IC50 of 17.2 and 13.1 hours, respectively.
Conclusions: Simulations were performed to assess study doses to maximize the number pediatric patients in various age ranges who achieve time above the IC50 (130 ng/mL) ≥ 6 hours. Optimized doses were 50 and 60 mg for ages 4-6, and 60 and 100 mg for the older cohorts to achieve presumed therapeutic target levels and reduce pill burden.
Citations: Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, [2021-2023][NHANES Questionnaires, Datasets, and Related Documentation ]
