Effect of Cytochrome P450 2D6 Genotype on Maternal Paroxetine Plasma Concentrations during Pregnancy

Background and Objective: Increasing numbers of women in childbearing years are treated with antidepressants. Concerns regarding fetal exposure to medication has led to large studies on drug effects on birth outcome and on the risk of congenital anomalies. The risk of adverse effects due to paroxetine use during pregnancy has been associated with the extent of exposure. Nevertheless, few studies have covered dosing aspects in order to minimize fetal antidepressant exposure while limiting the risk of treatment failure. Essential pharmacokinetic data in pregnancy are lacking, even regarding paroxetine, one of the most commonly used antidepressants. We examined the changes of maternal paroxetine concentrations during pregnancy in relation to cytochrome P450 (CYP) 2D6 genotype. Method: An observational cohort study was conducted in 74 pregnant women aged from 25 to 45 years treated with paroxetine during pregnancy. Blood samples and information on dosing, weight, smoking and mood were provided at 16-20, 27-31 and 36-40 weeks of pregnancy. Samples were analysed for paroxetine plasma concentrations and CYP2D6 genotype. Results: Women who were genotyped as extensive metabolizers (EMs) or ultra-rapid metabolizers (UMs) for CYP2D6 (EM n=43; UM n=1) showed steadily decreasing plasma paroxetine concentrations during the course of pregnancy, with a decrease of 0.3 mu g/L (95% CI -0.58, -0.07) for each week of pregnancy. In contrast, plasma paroxetine concentrations of intermediate metabolizers (IMs [n=25]) and poor metabolizers (PMs [n = 5]) increased during pregnancy, resulting in an increase of 0.82 mu g/L (95% Cl 0.42, 1.22) for each week of pregnancy. Weight gain, maternal age or smoking did not influence plasma drug concentrations. Decreasing plasma concentrations in EMs are in accordance with induced C-YT2D6 activity during pregnancy. Accumulation of paroxetine in women with impaired CYP2D6 metabolism may be explained by competition with an endogenous substrate. In EMs/UMs the depressive symptoms increased significantly during the course of pregnancy, while in the IM/PM group these did not change. Conclusions: Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient's CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy [trialregister. nl Identifier ISRCTN25383361].