Physiologically based pharmacokinetic modelling predicts altered maternal pharmacokinetics of amitriptyline during pregnancy

Aims: Pharmacotherapy of maternal peripartum depression is an increasing challenge. Amitriptyline (AMI) is the most often used tricyclic antidepressant during pregnancy, but knowledge on pharmacokinetics in this special phase is lacking. Physiologically based pharmacokinetic (PBPK) modelling is a powerful tool to better understand pregnancy-induced pharmacokinetic changes of medication. We aimed to improve the knowledge about AMI pharmacokinetics during pregnancy using PBPK modelling. Consequently, we aimed to add new information for an effective and safe pharmacotherapy in pregnant women. Methods: A PBPK model, including AMI, but also its active metabolite nortriptyline (NOR), was developed to investigate pregnancy-induced pharmacokinetic changes after AMI administration. The predicted drug exposure was compared to observed concentrations in pregnant patients in clinical routine. The PBPK model was set up using PK-Sim Version 11. Results: Serum concentration profiles were described successfully. During pregnancy, active moiety serum concentration of AMI (AMI + NOR) did not change; however, AMI concentration increased, whereas NOR concentration decreased. Conclusions: With this model, we added valuable information on AMI pharmacokinetics during pregnancy (increased AMI concentration, decreased NOR concentration). For clinical practice the treating physician should be aware that despite active moiety serum concentration comparable to before pregnancy, tolerability may be affected due to increased AMI serum concentrations and as consequence increased anticholinergic effects. To keep the risk of therapy discontinuation during pregnancy low, we suggest performing therapeutic drug monitoring, especially to check the AMI serum concentration.