2020
DOI: 10.1111/jphp.13281
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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 strategi… Show more

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Cited by 11 publications
(20 citation statements)
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References 53 publications
(76 reference statements)
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“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Methodsmentioning
confidence: 99%
“…A successful validation approach was assumed when Simcyp‐predicted results overlapped with the observed datasets (Almurjan et al. 2020; Olafuyi & Badhan, 2019).…”
Section: Methodsmentioning
confidence: 99%
“…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.…”
Section: Predictive Performancementioning
confidence: 99%