Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study

Abstract

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.

When special populations intersect with drug–drug interactions: Application of physiologically‐based pharmacokinetic modeling in pregnant populations

“…Exploration of DDI potential or the effects of enzyme genotypes on dosing regimens using pPBPK is a much‐needed application, due in large part to the impracticality and safety concerns of performing such clinical studies in pregnant populations. Our critical analysis of pPBPK modeling applications identified only one case with the specific purpose of investigating DDI (Olafuyi et al., 2017) and two investigated dosing paradigms for CYP2B6 and CYP2D6 poor versus ultra‐metabolizers (Almurjan et al., 2020; Chetty et al., 2020). Despite the wealth of knowledge currently available, at least for CYP enzymes, extensive application of pPBPK for prospective evaluation of DDI risk has yet to manifest.…”

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study

“…The Simcyp Pregnancy model does not inherently include longitudinal changes in CYPs 2C19 and 2B6, and these were incorporated based on previous reports of successful implementation within the Simcyp Simulator (Almurjan et al., 2020; Ke et al., 2018) (Supplementary Materials (Section 2). In order to replicate the study by Westin et al.…”

“…A successful validation approach was assumed when Simcyp‐predicted results overlapped with the observed datasets (Almurjan et al. 2020; Olafuyi & Badhan, 2019).…”

The Pharmacokinetics of Gefitinib in a Chinese Cancer Population Group: A Virtual Clinical Trials Population Study

“…In addition, a visual predictive checking (VPC) strategy was utilised where the predicted mean and 5th and 95th percentiles of the concentration−time profiles were visually compared with retrospective observed data, with the prediction assumed to be valid when the predicted data points overlapped with the observed data sets. [49][50][51] Data and statistical analysis All the observed data acquired from published studies was extracted by WebPlotDigitizer v.3.10 (http://arohatgi.info/WebPlotDi gitizer/). Statistical analysis was conducted with GraphPad Prism version 8.0 for Windows (GraphPad Software, La Jolla, CA, USA, www.…”