Physiologically based pharmacokinetic modeling of tapentadol in children to support pediatric dose selection

Tapentadol, an effective opioid analgesic, is indicated for the treatment of pain that cannot be managed with non-opioid medications. This study employed a physiologically based pharmacokinetic (PBPK) model to characterize the disposition of tapentadol in children across different age groups and to refine pediatric dosing strategies. Initially, an adult PBPK model was developed using the ‘middle-out’ strategy, which was then adjusted by scaling anatomical and physiological parameters to apply it to pediatric populations. The model's precision was confirmed by comparing the simulated plasma concentrations in a virtual population with empirical data. Utilizing this model, we translated dosages from adults to children and assessed weight-adjusted dosages for children aged 2 to 18 years and those under 2 years. The ratios of predicted to observed pharmacokinetic (PK) parameters for adult tapentadol ranged from 0.80 to 1.40 with the pediatric population's predictive mean absolute prediction error (MAPE) being less than 0.45. Based on model validation, we have established the following fixed-dose regimen for tapentadol oral solution for children across various age groups: 2.5 mg for 0–1 month, 3.5 mg for 1–3 months, 5 mg for 3–6 months, 8.5 mg for 6 months to 1 year, 13 mg for 1–2 years, 20 mg for 2–6 years, 35 mg for 6–12 years, and 60 mg for 12–18 years. The results of this study may offer guidance for the clinical investigation of tapentadol in pediatric patients and for developing PBPK models for drugs undergoing multiple metabolic pathways.