dataesr/scientific-paragraphs-categorization huggingface dataset:
Model performance TXA plasma Cp-time profiles were simulated using the relevant parameters detailed in Tables  2, 3 , 4 and 5. The full, predicted Cp-time profiles are shown compared to the observed data for each regimen evaluated in Fig. 3. The relevant summary statistics (Cmax, AUC, Tmax) and associated prediction errors (PE) are compared in Table  6. Across the populations, doses and routes of administration evaluated, the model performed with an average PE of 9 and 6% on Cmax and AUC0-t, respectively (Table  6 ). Considering the IV and oral validation dataset, both the predicted Cmax and AUC0-t are within 10% of the observed values (Xanodyne Pharmaceuticals Inc. , 2009). Regarding the observed Cmax in the  Sano et al. study, (SANO et al. , 1976)  and the high prediction error (48%), the infusion time is reported to be 4 min, however the first blood sample was not taken until T = 15 min.
PO Simulations Two simulated oral Cp-time profiles (PO Sim1 and PO Sim2) are presented in Fig. 4  (top left panel), both assume dosing of 4000 mg as a solution (40 mL of a 100 mg/mL) administered in the fasted state. A stomach transit time of 0. 1 h was used in both simulations, while PO Sim1 assumes a Peff of 0. 4 × 10-4 cm/s and PO Sim2 a Peff of 0. 5 × 10-4 cm/s. The permeability estimates used reflect (to 1. d. p) the highest and lowest values required to simulate the observed oral PK (Table  4  and Fig. 3 ) and for comparison the average Peff value of 0. 45×10-4 cm/s was used when simulating the oral validation dataset (Xanodyne Pharmaceuticals Inc. , 2009). The default human fasted advanced compartmental absorption and transit model (ACAT) was used and all other model parameters were as defined in Table  3  and Section 2.
SQ Simulations SQ Cp-time profiles were simulated for doses of 1000 mg initially but increased to 2000 mg in order to exceed the 15 µg/mL target concentration. In GastroPlus® the dose volume for a SQ administration is capped at 10 mL so for the 2000 mg simulation it was necessary to assume a 200 mg/mL solution of TXA was dosed, the feasibility of this concentration, from a formulation perspective, is unknown. The site of injection (SOI) was defined as adipose in the leg and as with IM dosing the same software limitations regarding the use of multiple injection sites applied. Therefore the minimum calculated depot volume of 74 mL was used in all SQ simulations. Human PK data following SQ administration of TXA has never previously been published, therefore the same strategy developed for the IM simulations was employed; default software estimates and three fold lower for adipose blood flow (2.
Discussion The present study describes the development of a PBPK model that can accurately describe single dose IV, oral (fasted and fed) and intramuscular administrations of TXA  (Chang et al. , 2004; Eriksson et al. , 1974; Pilbrant et al. , 1981; Puigdellivol et al. , 1985; SANO et al. , 1976; Sindet-Pedersen, 1987). PK data from six different single dose studies performed in healthy volunteers were utilised during model development. External validation of the model was performed for the IV and PO routes of administration and prediction errors on Cmax and AUC0-t were ≤ 10% for both routes  (Xanodyne Pharmaceuticals Inc. , 2009). Across study variability in PK was captured through demographic (ethnicity, gender, age and body weight) effects on GFR, Vss and key absorption parameters specific to the route of administration.
Intestinal permeability and stomach transit time were significant factors following oral dosing and muscle blood flow and partition coefficient were significant following IM dosing. The range of values estimated by this model for total plasma clearance are compatible with TXA clearance values reported elsewhere in healthy volunteers and in cardiac surgery patients  (Grassin-Delyle et al. , 2013; Nilsson, 1980; Pharmacia and Upjohn Co, 2020; Pilbrant et al. , 1981; Sharma et al. , 2012). No measured data was available on the blood to plasma ratio (Rbp) for TXA. Based on structure a Rbp of 1. 35 was predicted using the ADMET software (version 7. 2), however the data sets upon which these predictions are based are significantly smaller than for critical physical chemical properties such as Log P and pKa and higher variability in biological measures, such as Rbp, mean these predictions are not typically as accurate.
The predicted value was tested during method development but a value of 1. 0 better captured the observed volume of distribution. A potential limitation of this work may result from the reduced number of participants involved in some of the source PK studies and a lack of associated demographic information. In addition no published PK data following SQ administration of TXA was found and therefore SQ simulations were performed by applying the same strategies as developed during modelling of observed IM PK data. Other potential limitations include the fact that, apart from in the Sindet-Pederson study where 50% of the participants were female,  (Sindet-Pedersen, 1987)  all the participants in the model development studies were male, while the model validation study only included female subjects (Xanodyne Pharmaceuticals Inc.
, 2009). However for the validation dataset the predicted Cmax and AUC0-t were within 10% of the observed values, which does suggest that gender does not play a significant role in the PK of TXA. Finally, despite an extensive search for all eligible PK data it is possible that some relevant studies may have been missed. It is of note that using the Puigdellivol et al. data, the prediction error calculated for the IV AUC0-t was high, with the model over predicting the observed AUC0-t by 23%. This may be due to an under prediction of renal filtration in these participants which may be confounded by a lack of body weight information. The IV plasma levels reported by Puigdellivol et al. do stand out as lower and more variable than the other IV PK datasets evaluated during this work, however subject numbers in the Puigdellivol study were limited (n = 3) making it difficult to draw conclusions  (Puigdellivol et al.
, 1985). TXA is a high solubility compound, the oral bioavailability of which is limited by intestinal permeability. Oral bioavailability has been predicted to vary from 36 to 67% across the datasets evaluated and due to the absence of any significant first pass extraction in the liver or gut, oral bioavailability directly represents the fraction of drug absorbed (Fa). The oral bioavailability of the TXA regimens evaluated Pilbrant et al. were reported to be 33 and 34%, with our model predicting 36 and 38% respectively. Due to the low permeability of TXA even small differences in the effective human permeability (Peff) have been shown to have a significant effect on Fa. Whilst the high solubility of TXA means we would not expect formulation effects to limit the extent of exposure, certain formulation factors may influence the rate of absorption and while the European studies  (Pilbrant et al.
, 1981; Sindet-Pedersen, 1987)  used the same oral drug product (multiple 500 mg Cyklokapron tablets), the oral formulations used by  Chang et al. and Sano et al. are  unclear, as are the specific formulation details of the IR reference tablet dosed in the study  XP12B-101 (Xanodyne Pharmaceuticals Inc. , 2009). After PO administration, plasma TXA concentrations are predicted to exceed 15 µg/mL within 15-30 min, to peak at between 30 and 60 µg/ mL in 2 h and be maintained above 15 µg/mL for 5-6 h. The oral simulations presented here assumed rapid (0. 1 h) gastric emptying of a solution formulation which is considered to be a reasonable assumption. Slower gastric emptying would result in slower absorption. Comparitively there is more uncertainty associated with our IM predictions due to less data available for model development, significant variability in the two available datasets and the absence of an external validation dataset.
Model validation dataset: NDA 022,430 study XP12B-101, Xanodyne Pharmaceuticals Inc. , 2009. Table 2 PEAR physiology file settings. Source Route Population Weight Age Gender GFR (kg) (Yrs) (mL/s) 2 Eriksson, IV American 71 36 M 1. 919 Pilbrant Pilbrant PO American 86. 27 30 M 2. 005 Puigdellivol IV, American 85. 12 27 M 2. 038 IM Sano IV Japanese 76 50 M 1. 763 Sano IM Japanese 72 46 M 1. 797 Sano Sindet-Pedersen 1 PO PO Japanese American 60 70 39 25 M M 1 1. 876 2. 052 Chang PO Chinese 69. 14 30 M 1. 707 Validation IV, American 75. 22 30 F 2. 005 (XP12B- PO 101).
ACKNOWLEDGMENT We gratefully acknowledge the  ANR  ( ANR-15-CE29-0001 " Mount Indole " and  ANR-17-CE07-0050 " ArDCo "), the  Université Paris-Saclay , and the  CNRS  for financial support. We thank  Maxime Jarret  for preliminary studies on the 1,4-addition of malonate 3 onto dienal 6.
Collection of socio-demographic and diagnostic data: All data used in this study was obtained retrospectively from patient clinical records with authorization of the CNIL (Commission Nationale de l'Informatique et des Libertés) and Institutional Review Board (N°19. 10. 06). Participants were not interviewed or assessed with regards to this study. Following advice from the Institutional Review Board, informed consent was waived because of the retrospective nature of the study and the low risk for participants. During the course of the study, a poster was displayed within the unit to inform patients that a study was underway and to invite them to contact a physician for further information or to oppose their inclusion. Age, sex, family and work status, were collected at the time of the patient interview for clinical purposes.
Toxicity studies of DILI-causing compounds Compounds with various DILI potentials were screened. Therapeutic exposure concentrations (C max ) were extracted from previously published data  36. After 5 days of culture, Hepoid-HepaRG were treated with 1x, 5x, 20x, 50x and 100x of the respective drug concentrations during a total of 14 days excepted for amiodarone (CAS 1951-25-3) and ketoconazole (CAS 65277-42-1) for which the maximal concentration was 50x because of their poor solubility. Acetaminophen (CAS 103-90-2) was diluted in the medium, whereas others compounds were diluted in DMSO with maximal concentration of DMSO never exceeding 0. 4 %. Viability was assessed by measurement of cellular ATP content using the CellTiter-Glo 3D Assay (Promega). Compounds were considered hepatotoxic when the viability was reduced by at least 20 % compared to control with * p < 0.
mRNA analysis Total RNA was extracted using NucleoSpin RNA (Macherey-Nagel). RNAs were reverse-transcribed into cDNAs using the High Capacity cDNA reverse transcription kit (Applied Biosystems). RT-qPCR analysis was performed with the CFX384 Real-Time System (Biorad) using the SYBR Green PCR master mix (Applied Biosystems). GAPDH was used as the internal reference. For transcriptomic analysis, mRNAs were collected from HepaRG cultured in 2D (n = 5) or in 3D at day 4 (n = 5), day 15 (n = 5) and day 28 (n = 4). RNA samples were checked for degradation based on the RNA Integrity Number (RIN > 8). The RNA libraries were sequenced using the HiSeq 2500 (Illumina). Complementary RNA synthesis, hybridization and chip scanning were performed at the GenoBIRD platform (Nantes, FR). Data analysis was performed using R.
Isolated case reports and small case series have suggested that other nor/epinephrine-based decongestants may induce stroke  5  or acute coronary syndrome  6, 7  , leading to restrictions of use and guidelines recommending that patients with cardiovascular antecedents or risk factors not use these drugs  8. However, sound pharmacoepidemiological studies are lacking. This study was conducted at the request of the French medicines safety agency (Agence Nationale de Sécurité des Médicaments, ANSM) following case reports of cardiovascular events in users of decongestants in the national pharmacovigilance database  9.
Definition of cases. Eligible strokes consisted of a first lifetime occurrence of ischemic or hemorrhagic stroke (intraparenchymal, intraventricular, or subarachnoid) confirmed by computed-tomography or magnetic resonance imaging  16. Cases of subdural bleeding, intracranial aneurysms, cerebral vascular malformations, or severe cranial trauma that occurred < 15 days before were not considered in the present study. Eligible MIs consisted of a first lifetime occurrence of MI with at least two of the following criteria: (a) typical chest pain, (b) typical electrocardiogram abnormalities, and (c) elevated troponin levels  17. Patients with a history of angioplasty, coronary bypass surgery, or hospitalization were excluded. The results of biological tests, imaging, and performed procedures, data on comorbid conditions and body mass index, and disease severity and risk scores (Glasgow coma scale, HAS-BLED and NIHSS) were retrieved from the registries.
All analyses were conducted using SAS software version 9. 2 (SAS Institute, Inc. NC, USA). Ethics approval and consent to participate. All participants in the registries provided an informed consent for their registration and those interviewed for this study consented to being interviewed. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics review committee of Paris-Ile de France III. Data collection was approved by the French data protection authority. The study was conducted under the auspices of an independent scientific committee which approved the protocol, the statistical analysis plan, and the reports to the regulatory agencies. Thirteen pharmaceutical companies commercializing vasoconstrictors participated in the funding of the study; however, the PGRx registries within which cases were identified were assembled independently and funded by multiple sources.
Results A flow-chart presenting the process of selection of cases eligible for this study amongst the patients in the two registries is shown in Fig. 1. In the ACS registry, 2,368 patients met the inclusion criteria for this study; among them, 1394 (58. 9%) underwent a telephone interview (88 with or via their proxy). In the stroke registry, 2230 patients met the inclusion criteria for this study; among them, 1403 (62. 9%) underwent a telephone interview (236 with or via their proxy). The studied population consisted of 2797 interviewed patients. Data on the interviewed and non-interviewed patients are shown in Table  1. The only notable difference between these two groups of patients was the proportion of hemorrhagic stroke among strokes (6. 5% in interviewed, 12. 8% in not interviewed). Overall, 89 (3.
Acknowledgements We thank the members of the " PGRx-stroke " and " PGRx-MI" study groups  for their contribution:  Jean-Yves Le Heuzey ,  Jean Ferrieres ,  Didier Leys ,  Jean-Marc Davy ,  Mikel Martinez ,  Didier Smadja ,  Emmanuel Ellie ,  Denis Sablot ,  Norbert Nighoghossian ,  Gregory Schoukroun ,  Olivier Gaillard ,  Stephane Fol ,  Henri Malaterre ,  Jean-Yves Tabet ,  Jacques Soulam ,  David Dedola ,  Benoit Spillemaecker ,  Ghazaleh Esna ,  Pierrick Boyer ,  David Ennouchi ,  Thierry Allaouchiche ,  Denis Guillemet ,  Alain Lacroix ,  Eric Espaliat ,  Pierre Duron ,  Eric Pichon ,  Philippe Dematteo ;  Olivier Nallet ,  Charlotte Mestrallet ,  Nicolas Delarche ,  Basel Koujan ,  Florence Leclercq ,  Michel Ovize ,  Jean-Yves Tabet ,  Adnan El Jabali ,  Philippe Meurin ,  Bruno Vaquette ,  Michel Martelet ,  Joseph Mouallem ,  Amavi Didier Kassehin ,  Hélène Kremer ,  Didier Pacaud ,  Olivier Lozinguez ,  Philippe Jessen ,  Alain Furber ,  Nathan Messas ,  Pierre Gueranger ,  Olivier Dibon ,  Olivier Morel ,  Nacera Abbou ,  Sébastien Terrazzoni ,  Jean-Paul Guillot ,  Jean-Baptiste Berneau ,  Julie Peroz-Froz ,  Yves Biron ,  Fahmi Ghanem ,  Michel Mansour ,  Jean-Philippe Mouret ,  Stéphane Greciano ,  Karine Mear ,  Ramzi Abi Akar ,  Étienne Puymirat ,  Nicolas Baron ,  Anthony Scemama ,  Michel Barboteu ,  Marc Goralski ,  Franck Albert ,  Patrick Bert Marcaz ,  Jean-Marie Gil ,  Philippe Chapon ,  Saed Jazayeri ,  Abdellatif El Hallak ,  David Bertora ,  Philippe Commeau ,  Virgile Yadouleton ,  Olivier Varenne ,  Le Anh Tuan Nguyen ,  Émile Ferrari ,  Corine Aboa-Eboulé ,  Nachwan Ghanem ,  Cécile Lacote Roiron ,  Audrey Duchemin ,  Adi Issa ,  Margarita Baert ,  Alireza Samadi ,  Wael Yafi ,  Christophe Piot ,  Thierry Joseph ,  Anne-Lise Gugenheim ,  Ciprian Anton ,  Éric Decoulx ,  Katy Didier-Petit ,  Gabriel Steg ,  Lyassine Nait Saidi ,  Tewfik Benchaa ,  Dr Sébastien Armero ,  Claudine Carville ,  Michel Marsaux ,  Éric Forest ,  Stéphane Fol ,  Agnès Holeman ,  Maurice Fauvel ,  Patrick Dary ,  Clément Unal ,  Christian Lorentz ,  Alain Pleskof ,  Codin Olariu ,  François-Xavier Meriaux ,  Olivier Azzano ,  Arnauld Dupoizat ,  Jean-Christophe Louchart ,  Grégory Schoukroun ,  Didier Lefevre ,  Guillaume Rosey ,  Guillaume de Geeter , and  Thibaud Meuric.
Extensive literature research on CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5, CYP3A7 activity. Open source OpenCYP database provides data for healthy adult variability in CYP activities. Quantitative comparisons are hampered by different experimental conditions used. Data gaps identified on specific age groups (e. g. elderly, children and neonates). OpenCYP database as a promising tool for PBk modelks and chemical risk assessment.
e. PBK and PBD models). The report identified, through consultations of national and international public health agencies, key priorities to implement such new approach methodologies (NAMs) in the risk assessment process  (EFSA, 2014). From these key priorities, EFSA launched a number of collaborative research projects including the creation of open source toxicological databases such as EFSA OpenFoodTox and related in silico models  (Dorne et al. , 2017 (Dorne et al. , , 2021;; Benfenati et al. , 2020)  as well as generic open source PBK models for human health, animal health and ecological risk assessment  (Grech et al. ; , 2019; Baas et al. , 2018; Lautz et al. , 2020a,b,c). A key strategy to implement these tools in chemical risk assessment is to move from external exposure metrics to internal dose metrics using TK parameters.
g PharmGKB and PharmVar Consortium) or sensitivity to adverse effects resulting from exposure to xenobiotics. In order to address the variability in the metabolic activity of CYP isoforms, this manuscript describes the results of extensive literature searches and critical data collection to investigate human variability in metabolic activities and relevant genetic polymorphisms in world populations of CYP isoforms in healthy adults, namely CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5 and CYP3A7. Results are presented in the open-source database OpenCYP. Future perspectives conclude particularly to explore the use of such database to develop QIVIVE extrapolations models fro chemical risk assessment.
Materials and methods Extensive Literature Searches (ELS) were performed using the methodology described in the EFSA Systematic Review Guidance (EFSA Guidance, 2010). The ELS was performed (January 1989 -October 2019) from the primary peer-reviewed scientific literature on CYP isoform activities looking into databases and multidisciplinary platforms of international coverage, namely Scopus, Web of Science, PubMed, Food Sience Source and Agricola. The ELS were carried out through the formulation of appropriate queries, exploiting the use of specific key terms for each topic and Boolean operators (eg. AND, OR, NOT), using different specific syntax for each database, designed to include as many studies as possible relevant to the scope and to minimise the bias (Table  1 ).
Data extraction Data from eligible studies after the secondary screening were extracted and captured in a data extraction form, organised in a structured Excel database, adapted from OECD harmonised templates (OHTs) from an EFSA's data model allowing consistency with EFSA's chemical hazards database (OpenFood-Tox)  (Dorne et al. , 2017). Reviews, book chapters and other sources not reporting primary datasets for CYP activity were not considered for data extraction to avoid multiple inclusion of the same dataset from different references. The database was structured as a single excel sheet showing in sequential order the data extracted from the selected papers: each study was identified with an ID number and information extracted included references, CYP isoform activity, details of the study design and method used (e.
g. probe substrate(s), methods for quantification of the parent/metabolite(s), matrix in which the metabolites were measured, time of treatment), number of individuals, summary statistics of in vivo parameters (e. g. sample size, arithmetic or geometric mean, median, standard deviation, confidence intervals, etc. ) and factors impacting on variability (e. g. world populations, presence of polymorphic enzymes) (Supplementary Material A). Whenever papers compared data between i) healthy adults (e. g. control group) vs individuals affected by specific diseases, or ii) healthy adults (e. g. control group) vs individuals taking specific medication or occupationally exposed, data from the control group were used, while data referring to the patients or 'exposed' people were flagged into the database by using a separate note column (pathologies or exposure type, respectively) as additional information.
Meta-analyses of TK data For the in vivo probe substrates identified from the ELS, data from human PK studies following oral (single) or intravenous (bolus) exposure to derive kinetic parameters such as Cmax, area under the curve-AUC and clearance were collected for CYP2A6 and 1A2. The search was carried out with the above mentioned criteria, to evaluate the possibility of performing a meta-analysis, aimed at estimating the distributions of variability for these two CYP activities in non-phenotyped subjects for each probe substrate and deriving the related variability distributions and uncertainty factors, following the method described in  Darney et al. (2019).
Overview of the OpenCYP database The whole data collection strategy and information flow of information for the six selected CYP isoforms namely CYP1A2, CYP2A6, CYP2D6, CYP3A4, CYP3A5, CYP3A7 is summarised in Fig. 1. As expected, the largest datasets were available for the major CYP3A subfamily and CYP3A4 isoform, CYP1A2 and CYP2D6, while datasets for CYP2A6 and CYP 3A5/3A7 isoforms were much more limited (Fig. 2 ). Overall, a total number of 121 papers providing quantitative data on isoform-specific CYPs activities and polymorphism frequencies across world populations were extracted and computed in the OpenCYP excel database (Supplementary material A and DOI for EFSA knowledge junction: 10. 5281/zenodo. 5031737). The complete list of relevant articles available in the database is provided in Supplementary material B.
, 1992; Wenk et al. , 2004; McCune et al. , 2001; Markowitz et al. , 2003a,b,c; o'Connell et al. , 2006; Tushar et al. , 2007; Al-Jenoobi et al. , 2014a , b, 2015; Saruwatari et al. , 2014). Historically, a urinary MR (DEX/DOR) !0. 3 has been generally applied to define PM phenotypes. From this database, the  Funck-Brentano et al. (1992)  enrolled 110 individuals of which 52 individuals were also genotyped: results indicated that both CYP2D6 EM and PM phenotypes were identified from the DEX/DOR MR calculated in urine. On the other hand, other studies showed that dextromethorphan metabolic ratio did not reliably discriminate heterozygous and homozygous EMs  (Evans and Relling, 1991). Grouping of datasets using the average DEX oral dose (30 mg), the mean urinary MRs for DEX (collected after 8 h) were 0.