PII-114 - RELATIVE IMPACT OF CYP2D6 GENOTYPE PHENOTYPE ON EXPOSURE OF SSRIS DURING PREGNANCY: EXTRAPOLATION APPROACH USING RWD AND PBPK MODELLING

K. Rowland-Yeo¹, E. Gil Berglund², P. Coppola³; ¹Certara UK, N/A, UK, ²Certara NL Ltd, Leiden, Netherlands, ³Certara Italy Srl, Rome


Lazio, Italy.

Background: Pregnancy and associated physiological changes can affect the pharmacokinetics (PK) of selective serotonin reuptake inhibitors (SSRIs) which are first--line treatment for depression. Some SSRIs are metabolised extensively by CYP2D6, whose expression is increased significantly during pregnancy [1]. Almost 21% of SSRI-treated women remained depressed during pregnancy (14.4% genetically normal or ultrarapid metabolizers (EM/UM) versus 6.1% poor or intermediate metabolizers (PM/IM)) [1]. The aim of this work was to use PBPK modelling along with RWD on SSRI exposures measured during the 3 trimesters of pregnancy (CYP2D6 genotypes not specified) to extrapolate to pregnant subjects of differing CYP2D6 genotypes. Metoprolol was used as the model CYP2D6 substrate as clinical data in CYP2D6-genotyped pregnant subjects were available [3].

Methods: Simulations were run to estimate metoprolol CL/F values during early and mid to late pregnancy for CYP2D6 UM, EM, IM and PM subjects and compared against observed data [2]. These relative changes were then compared against RWD [2] indicating reduced exposures of SSRIs (venlafaxine, sertraline, paroxetine, fluvoxamine), in pregnant subjects.

Results: In CYP2D6 EM and IM subjects, predicted metoprolol CL/F (L/h/kg) values were within 1.25-fold of observed data in mid to late pregnancy and post-partum. For EM/UM subjects, the change in metoprolol CL/F during pregnancy relative to non-pregnancy was 1.34-, 1.81- and 2.46-fold for trimesters 1, 2 and 3, respectively, which reflect the reported changes in SSRI exposures (average values of 1.14-, 1.57- and 2.15-fold for each of the trimesters, respectively) [3]. Of particular note, is the fact that predicted metoprolol CL/F values for UM subjects were 15.9-, 19.8- and 24.3-fold higher than for PM subjects during the 3 trimesters.

Conclusion: The findings indicate that prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation due to inefficacious treatment. PBPK modelling could be used to guide dose adjustments during pregnancy based on CYP2D6 genotype.