Open AccessPrecision dosing‐based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study
Author(s) -
Almurjan Aminah,
Macfarlane Hannah,
Badhan Raj K. S.
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13281
Subject(s) - pharmacokinetics , gestation , dosing , paroxetine , cyp2d6 , medicine , pharmacology , pregnancy , trough concentration , endocrinology , biology , metabolism , genetics , cytochrome p450 , antidepressant , hippocampus
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.