Virtual twin approach using physiologically based pharmacokinetic modelling in hospitalized patients treated with apixaban or rivaroxaban

Article Article scientifique Article Virtual twin approach using physiologically based pharmacokinetic modelling in hospitalized patients treated with apixaban or rivaroxaban eng 2025-03-04 author Gaspar Frédéric 0000-0002-0225-7294 Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western (ISPSO) Switzerland, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 781664 author Terrier Jean 0000-0002-5878-4878 Division of General Internal Medicine, Geneva University Hospitals (HUG), Geneva, Switzerland.,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 536564 author Jacot-Descombes Célestin School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 941027 author Gosselin Pauline Division of General Internal Medicine, Geneva University Hospitals (HUG), Geneva, Switzerland. 804518 author Ardoino Valentine School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 927770 author Lenoir Camille 0000-0001-6506-8629 Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 777980 author Rollason Victoria 0000-0002-8073-6610 Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 40955 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Csajka Chantal 0000-0002-0660-082X Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Institute of Pharmaceutical Sciences of Western (ISPSO) Switzerland, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 657943 Section des sciences pharmaceutiques (FARMA) author Samer Caroline Flora 0000-0001-8178-0616 Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 105661 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Fontana Pierre 0000-0003-1546-0774 Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Division of Angiology and Haemostasis, Geneva University Hospitals (HUG), Geneva, Switzerland. 135328 Département de médecine (DEMED) author Daali Youssef 0000-0002-8391-9383 Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency, Geneva University Hospitals (HUG), Geneva, Switzerland. 46042 Département d'anesthésiologie, pharmacologie et soins intensifs (APSIC) author Reny Jean-Luc 0000-0002-7528-7363 Division of General Internal Medicine, Geneva University Hospitals (HUG), Geneva, Switzerland.,Geneva Platelet Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 704339 Département de médecine (DEMED) OptimAT study group bcp.70032 10.1002/bcp.70032 40035306 0306-5251 https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/bcp.70032 Aims: In a large cohort of hospitalized patients, previously validated physiologically based pharmacokinetic (PBPK)-based models for apixaban and rivaroxaban are being assessed for their performance in predicting individual pharmacokinetics, aiming to identify patients at high risk of under- or overdosing based on demographic, physiological and CYP-related phenotypic characteristics. Methods: Clinical data were collected from hospitalized patients treated with apixaban (n = 100) or rivaroxaban (n = 100) at the Geneva University Hospitals (HUG). These patients were recruited in the OptimAT trial (<a href="http://clinicaltrials.gov/show/NCT03477331" rel="noopener noreferrer" target="_blank">NCT03477331</a>). PBPK modelling created virtual twins for each patient, integrating demographic, kidney function, P-glycoprotein (Pgp) and cytochrome P450 (CYP450) 3A phenotyping. Individual PK profiles were simulated for every patient and compared to actual drug exposure, as assessed with LC/MS-MS. Results: Mean fold error (MFE) (95% CI) for the apixaban and rivaroxaban models integrating demographic and kidney function was within the pre-required bioequivalency criteria with 1.10 (1.04-1.16) and 0.97 (0.93-1.02), respectively. Adding individual Pgp and CYP3A phenotypes led to a slight overprediction 1.25 (1.17-1.33) and 1.30 (1.21-1.39), but patients at risk for bleeding were correctly predicted with MFEs of 0.90 (0.76-1.04) and 1.15 (1.11-1.20). Conclusions: In a large cohort of hospitalized patients, a PBPK model incorporating demographic characteristics and kidney function can accurately predict, within bioequivalency criteria, an individual's apixaban and rivaroxaban plasma exposure. The added value of individual Pgp and 3A phenotypes on the predictive performance need to be further explored, although patients at higher risk for bleeding may benefit. This innovative approach represents an important step towards the application of PBPK at bedside. © 2025 British Pharmacological Society. PBPK Apixaban Direct oral anticoagulant Physiologically based pharmacokinetics Rivaroxaban Dewey 615 Dewey 616 Dewey 617 31 Section des sciences pharmaceutiques 17 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 56 Département de médecine 221 false 302 Groupe Desmeules Jules (pharmacologie/toxicologie) 567 1280 Pharmaco-omiques et médecine de précision 1003 1440 Infections de la personne âgée 1062 11 Plaquettes et antithrombotiques 13 319 Groupe Perrier Arnaud (Médecine interne générale, de réhabilitation et de gériatrie) 585 887 Pharmacie hospitalière et clinique British journal of clinical pharmacology eda16cc9-16b5-4139-90ac-287bfa45c884 Article (Published version) Restricted Brit_J_Clinical_Pharma_-_2025_-_Gas.pdf 2349526 application/pdf 61dd43fcb35ffb1744a92ad6f540b3c48518cb260b7917a6f1d9247c0ef0d7a9 66d4811e-7fb8-4334-8823-320bd813574c Supplemental data Restricted bcp_70032-sup-0001-supplementary.docx 123756 application/vnd.openxmlformats-officedocument.wordprocessingml.document Table S1-S9 274af5b53fe1feb0298494fb331e97d0f039f0f060feb07c29e8a161eff57dd2 restrictedAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté de médecine / Section de médecine clinique / Département de médecine

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Virtual twin approach using physiologically based pharmacokinetic modelling in hospitalized patients treated with apixaban or rivaroxaban	British journal of clinical pharmacology			2025	88	1

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