2006 - Brugge/Bruges - Belgium

PAGE 2006: Applications
Walter Woltosz

Simulation of the Nonlinear PK of Gabapentin and Midazolam in Adult and Pediatric Populations

Woltosz, Walter S. and Michael B. Bolger

Simulations Plus, Inc.

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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.

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

Reference: PAGE 15 (2006) Abstr 982 [www.page-meeting.org/?abstract=982]
Oral Presentation: Applications