Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population
Received 12 March 2019
Accepted for publication 26 July 2019
Published 14 October 2019 Volume 2019:12 Pages 2835—2850
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Dr Katherine Hanlon
Estelle Watson,1 Akash Khandelwal,1 Jan Freijer,1 John van den Anker,2,3 Claudia Lefeber,1 Mariëlle Eerdekens1
1Grünenthal GmbH, Aachen, Germany; 2Division of Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland; 3Division of Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA
Correspondence: Estelle Watson
Grünenthal GmbH, Zieglerstraße 6, 52078 Aachen, Germany
Tel +49 241 569 2141
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.
Keywords: tapentadol, pediatric, pain management, dosing, nonlinear mixed effects modeling
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