Application of Physiologically-Based Pharmacokinetic model To Predict Tramadol Concentration in human Milk
Khaled Abduljalil (1), Trevor N. Johnson (1), Masoud Jamei (1)
(1) Simcyp LTD (a Certara Company), Sheffield, UK
Objectives: To use a Physiologically-Based Pharmacokinetic (PBPK) model for prediction of Tramadol milk concentration in mothers with different CYP2D6 Phenotypes.
Methods: A predictive PBPK model was developed based on physiological and drug specific parameters (Fleishakeret al 1987) to predict tramadol concentration in 100 extensive metabolizers (EM CYP2D6) lactating mothers after twice daily administration of 333umol (100 mg). The compound model was developed in the Simcyp Simulator V16 and the lactation model coded using the Simcyp Lua scripting functionality. Predictions of milk concentration in other CYP2D6 phenotypes were performed and compared to EM mothers. The relative infant daily dose (RID) is calculated form the predicted milk concentration in different phenotypes.
Results: The model replicated the clinical observation adequately in EM mothers during lactation at steady state. Predicted milk-to-plasma (M/P) ratio was 1.87±0.06 (vs observed 1.9 (Salman et al., 2011)). The calculated AUC12h for tramadol in milk at steady state were 43882, 28190, and 21196 nmol/L*hr for PM, EM and UM respectively. The predicted RID (%) was 5.18±1.47, 3.98±1.19, and 3.31±1.08 for PM, EM and UM, respectively.
Conclusions: PBPK models can be used to predict M/P ratio and its inter-subject variability using the drug physicochemical properties and system (mother and lactation) parameters. While, the predicted RID for tramadol was below 10% of maternal dose, it may pose potential risk if mothers are poor metabolizers or for a given phenotype take higher doses. The PBPK model can be used to explore additional scenarios, such as DDIs, dose modification and/or incorporating metabolites data.
References:
[1] Fleishaker JC, Desai N, McNamara PJ. Factors affecting the milk-to-plasma drug concentration ratio in lactating women: physical interactions with protein and fat. J Pharm Sci. 1987 Mar;76(3):189-93.
[2] Salman S, Sy SK, Ilett KF, Page-Sharp M, Paech MJ. Population pharmacokinetic modeling of tramadol and its O-desmethyl metabolite in plasma and breast milk. Eur J Clin Pharmacol. 2011 Sep;67(9):899-908.