Model-informed Evidence Approach For Paediatric And Neonate Dosing Of Tramadol

• By: CICALI, Brian (University Of Florida, United States)
• Co-author(s): Dr Brian Cicali (University Of Florida, Ocala, United States)
  Dr Rodrigo Cristofoletti (University Of Florida, Ocala, United States)
  Dr Pieter Annaert (KU Leuven, Leuven, Belgium)
  Dr Karel Allegaert (KU Leuven, Leuven, Belgium)
  Dr Stephan Schmidt (University Of Florida, Ocala, United States)
  
• Abstract:

  Tramadol is a useful medication to treat postoperative pain in children, including neonates and infants. Tramadol has complex pharmacokinetics, which makes identifying the ideal dosage for these populations challenging. Specifically, these challenges include age-based physiological changes, enzyme expression variability, and active metabolites. The approved indication of tramadol in these populations varies greatly by country, yet off-label use for postoperative pain in these patient populations is common. Therefore, this project focused on bridging the knowledge gap of neonate and infant tramadol pain management care through mechanistic modelling methods which incorporated age-based physiological changes to compare tramadol exposure across age groups (neonates, infants, children, and adults) for dose optimization. In lieu of dedicated clinical trials in these vulnerable populations, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model, which incorporated both intrinsic and extrinsic population properties to accurately predict tramadol exposure after oral or IV administration. Specifically, the final model incorporated enzyme (CYP2D6, UGT2B7) and transporter (OCT1) expression data, active metabolite generation/exposure, developmental age-based changes in physiology, and tramadol physiochemical properties. Model simulation results indicated a significant age-based exposure trend for tramadol and its active metabolite. The effect of these exposure changes was evaluated using an Emax pharmacodynamic model, under the assumption that the exposure-response relationship of tramadol and its active metabolite remains the same amongst all age groups. The results of these PBPK/PD analyses suggested the dose-exposure-response relationship was not equivalent among these populations, but this nonequivalence could be alleviated via dose decreases based on age, e.g. 2 mg/kg in children (2-7 years), 1 mg/kg in infants (1 month-2 years), and 0.60 mg/kg in neonates (< 1 month). Overall, by utilizing a physiologically based modeling approach we were able to quantify differences in tramadol and active metabolite exposure-response amongst varying age groups, including neonates and infants. This suggests that dosing can be optimized based on these differences. Future work will focus on further validating these dose optimization findings in the context of clinical practice.