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.
 Gidal, B. E. et al, Epilepsy Res 40:123 (2001)
 Uchino, et al, Molec Pharmacol 61:4 (2002)
 Paine, et al, J Pharmacol Exp Ther 283:3 (1997)
 Johnson, et al, Br J Clin Pharmacol 51:5 (2001)
 Kupferschmidt, et al, Clin Pharmacol Ther 58:1 (1995)
 Oullet, D. et al, Epilepsy Res 47:229 (2001)
 Johnson, et al, Br J Anaesth 89:3 (2002)