Objective: Paroxetine has been demonstrated to undergo gestation-related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. Methods: A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20–60 ng/ml. Key findings: A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultrarapid (UM) phenotype subjects possessed trough levels below 20 ng/ml (73–76%) compared to extensive metabolisers (EM) (51–53%). Conclusions: For all phenotypes studied, there was a requirement for daily doses in excess of the standard 20 mg dose throughout gestation. For EM, a dose of 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3 is suggested to be optimal. For poor metabolisers (PM), a 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3 is suggested to be optimal. For UM, a 40 mg daily dose throughout gestation is suggested to be optimal.
Bibliographical noteThis is the peer reviewed version of the following article: Almurjan, A., Macfarlane, H. and Badhan, R.K.S. (2020), Precision dosing‐based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study. J Pharm Pharmacol, which has been published in final form at https://doi.org/10.1111/jphp.13281. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
- physiologically based pharmacokinetic
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Student thesis: Doctoral Thesis › Doctor of PhilosophyFile