Population-based PBPK modelling was conducted using the virtual clinical trials simulator Simcyp (Simcyp Ltd., a Certara company, Sheffield, UK, Version 16). Simulations were performed for an exclusive CYP2C19 extensive metaboliser (EM) (CYP2C19*1/*1), poor metaboliser (PM) (CYP2C19*2/*2), intermediate metaboliser (IM) (CYP2C19*1/*2) and ultrarapid metaboliser (UM) (CYP2C19*1/*17) population groups. For all simulations, dosing occurred under fasted-conditions unless otherwise indicated. A detailed list of haplotypes associated with GOF or LOF alleles are detailed within the PharmGKB database (Accession number: PA124) [19 ].
Simcyp
Manufactured by Certara
Sourced in United Kingdom, United States
Simcyp is a leading physiologically-based pharmacokinetic (PBPK) modeling and simulation platform. It provides a comprehensive in silico platform for predicting the absorption, distribution, metabolism, and excretion (ADME) of drugs and chemicals in virtual patient populations.
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Lab products found in correlation
8 protocols using simcyp
1
Pharmacogenomic Simulation of CYP2C19 Variants
2
PBPK Modeling for Pediatric Populations
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All population based PBPK modelling was conducted using the virtual clinical trials simulator Simcyp® (Simcyp® Ltd, a Certara company, Sheffield, UK, Version 16) using either the prevalidated in-built 'Healthy Volunteer' or 'Paediatric' population groups. The latter population group accounts for age-related changes in systems-parameters such as organ volumes, organ perfusion and ontogeny of drug metabolising enzymes [29] [30] [31] and allows for the prediction of drug behaviour in paediatric population groups . In the case of both models, population variability is accounted for by the inclusion of a variability metric (% coefficient variability) having been established from public health data bases such as the US National health and Nutrition Examination Survey (https://www.cdc.gov/nchs/nhanes/).
3
Age-based Balovaptan Dosing for Pediatric ASD
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The final PopPK model was used to simulate alternative age-based balovaptan dosing scenarios in a pediatric and adult population with ASD aged 2 years and above. Age–weight–sex distributions were sampled from a large database comprised of the participants from the aV1ation and VANILLA trials together with 1000 virtual participants aged 2–25 years from a pediatric and adult ASD population that was simulated in Simcyp (Certara, Inc., Princeton, NJ, USA).
Three-thousand individual PK profiles were simulated to derive steady-state area under the curve (AUCss) for each dosing scenario. The target scenario was an AUCss distribution that was homogeneous across the pediatric age range and equivalent to adult exposure at all ages. Based on the results from these simulations, an updated age-based dosing algorithm was proposed for future studies of balovaptan in pediatric participants aged 2 years and above.
Three-thousand individual PK profiles were simulated to derive steady-state area under the curve (AUCss) for each dosing scenario. The target scenario was an AUCss distribution that was homogeneous across the pediatric age range and equivalent to adult exposure at all ages. Based on the results from these simulations, an updated age-based dosing algorithm was proposed for future studies of balovaptan in pediatric participants aged 2 years and above.
4
ADAM Pharmacokinetic Simulation of Sorafenib
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Sorafenib absorption was simulated using the advanced dissolution, absorption, and metabolism (ADAM) sub-model which incorporates membrane permeability, intestinal metabolism and transporter-mediated uptake and efflux. The ADAM sub-model was used in conjunction with a full-body PBPK model, containing compartments and drug distribution characteristics for all organs. All simulations were performed using Simcyp® (version 19.1, Certara, UK). The differential equations underpinning the model have been described previously [42 (link)].
5
Epirubicin PBPK Modeling and Simulation
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A full-body PBPK model to simulate the concentration time profile for epirubicin following a single IV dose infused over 3 min was developed using Simcyp® version 19.1 (Certara, Sheffield, UK). The differential equations utilised by Simcyp to construct the PBPK model from physiochemical and in-vitro data have been described previously by [30 (link)].
6
In Vitro-In Vivo Data Analysis for Lactational Transfer
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Clinically observed M/P data were collected from published literature (Yang, Xue et al.). Experimental values of fraction unbound in plasma (fup) and fraction unbound in milk (fum) data were collected from literature (Yang, Xue et al.). Fni,7.4 and Fni,7.0 were predicted by a prediction toolbox (Fni module) in SimCYP (version 20, Certara USA Inc., Princeton, NJ, USA). The efflux ratios in Caco-2 cells were collected from literature (Yang, Xue et al.).
7
Population-based PBPK Modeling of Lumefantrine and Efavirenz
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Population based PBPK modelling was conducted using the virtual clinical trials simulator Simcyp (Simcyp Ltd., a Certara company, Sheffield, UK, Version 16). For all simulations, doses for both lumefantrine and efavirenz were employed according to the standard weightbased dose regimen (See supplementary materials table S1), unless stated otherwise. Further, for all lumefantrine simulations, dosing occurred under fed-conditions unless otherwise indicated.
A C C E P T E D M A N U S C R I P T 6
A C C E P T E D M A N U S C R I P T 6
8
PBPK Modeling of Chloroquine Pharmacokinetics
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The virtual clinical trial simulator Simcyp (Simcyp® Ltd., a Certara company, Sheffield, UK, version 16) was used to create all the population-based PBPK models used in this study through the implementation of a prevalidated "healthy volunteer" (HV) population. For simulations requiring the use of pregnant subjects, we used the Simcyp "Pregnancy" population group, [38] [39] [40] which incorporates gestational phaseedependant physiological changes associated with pregnancy that may alter the PK of drugs such as a change in blood volume and organ/tissue blood flows and change in enzyme/protein expressions. 38, [41] [42] [43] [44] [45] A 3-stage workflow model was used and is detailed in Figure 1. We adopted a robust validation approach using 16 clinical studies for CQ, a summary of which is described within the Supplementary Material (Section A, Table S1). Furthermore, unless otherwise stated, population sizes used in simulations of validation steps and those used within steps 3 included a 10 Â 10 trial design with 100 subjects.
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