Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population.

OBJECTIVE

The main aim of this analysis was to characterize the pharmacokinetics (PK) of the strong analgesic tapentadol in 2-year-old to <18-year-old patients with acute pain and to inform the optimal dosing strategy for a confirmatory efficacy trial in this patient population.

METHODS

The analysis dataset included tapentadol concentrations obtained from 92 pediatric patients receiving a single tapentadol oral solution (OS) dose of 1.0 mg/kg bodyweight in two single-dose PK clinical trials. Population PK analysis was performed using nonlinear mixed effects modeling. Simulations were performed to identify tapentadol OS doses in pediatric subjects (2 to <18 years) that would produce exposures similar to those in adults receiving safe and efficacious doses of tapentadol IR (50-100 mg every 4 hrs).

RESULTS

Tapentadol PK in children aged from 2 to <18 years was best described by a one-compartment model. Mean population apparent clearance and apparent volume of distribution for a typical subject weighing 45 kg were 170 L/h and 685 L, respectively. Clearance, expressed in bodyweight units as L/h/kg, decreased with increasing age whereas total clearance (L/h) increased with increasing age. Model-based simulations suggested that a tapentadol OS dose of 1.25 mg/kg to children and adolescents aged 2 to <18 years would result in efficacious tapentadol exposures similar to those in adults receiving tapentadol immediate release 50-100 mg every 4 hrs. The proposed tapentadol OS dose was subsequently applied in a confirmatory efficacy trial in 2 to <18-year-old patients suffering from acute postsurgical pain.

CONCLUSION

This analysis provides an example of a model-based approach for a dose recommendation to be used in an efficacy trial in the pediatric population. Uniform dosing based on bodyweight was proposed for the treatment of acute pain in children aged from 2 to <18 years.