Simulation of the Nonlinear PK of Gabapentin and Midazolam in Adult and Pediatric Populations
Woltosz, Walter S. and Michael B. Bolger
Simulations Plus, Inc.
Objective: Demonstrate building GastroPlus(tm) models for the nonlinear dose dependencies for gut transporter and gut enzyme substrates in adult and pediatric populations.
Methods: For both drugs, tissue weights, volumes, and perfusion rates were generated by the Population Estimates for Age-Related Physiology(tm) (PEAR) module in GastroPlus(TM) (Simulations Plus, Lancaster, CA). Adult Gabapentin renal clearance was estimated from creatinine clearance [Gidal, 2001]. Gabapentin undergoes saturable absorption via the LAT-1 amino acid transporter [Uchino, 2002]. GastroPlus(tm) was used to fit the nonlinear, regionally dependent absorption of gabapentin from data for a 400 mg solution dose in adults. Adult simulations for 400-1600 mg solid dosage forms validated the model. Adult Midazolam simulations employed microsomal Vmax and Km for 3A4 metabolism [Paine, 1997]. Midazolam 3A4 Vmax was adjusted for pediatric subjects based on literature data for 3A4 expression levels in children [Johnson, 2001]. Simulation results were compared to literature data for similar populations.
Results: GastroPlus simulations accurately reproduced the nonlinear dose dependencies for 400-1600 mg doses of Gabapentin and 7.5-30 mg doses of Midazolam in adults [Kupferschmidt, 1995]. Using a purely in silico generated population of pediatric subjects, the distribution of both gabapentin and midazolam Cp-time profiles for pediatric populations closely matched those observed in vivo [Oullet, 2001; Johnson, 2002].
Conclusions:: Following calibration of a physiologically-based gastrointestinal simulation for adult physiology, a purely in silico estimation of pediatric physiology and tissue:plasma partition coefficients could be used to predict the pediatric Cp vs. time profile for Gabapentin and Midazolam following oral liquid or capsule administration.
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