Edouard Ollier1,2,3, Sophie Hodin4, Julien Lanoiselée5,4, Jean Escal5,4, Sandrine Accassat4,6,7, Elodie De Magalhaes5,8, Thierry Basset5,4, Laurent Bertoletti5,8,6, Patrick Mismetti5,8,6, Xavier Delavenne5,4,6. 1. INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France. ed.ollier@gmail.com. 2. Laboratoire de Pharmacologie Toxicologie, INSERM UMR1059, CHU de Saint-Etienne, Hôpital Nord, 42055, Saint-Étienne, France. ed.ollier@gmail.com. 3. Université Claude Bernard Lyon 1, Villeurbanne, France. ed.ollier@gmail.com. 4. Laboratoire de Pharmacologie Toxicologie, INSERM UMR1059, CHU de Saint-Etienne, Hôpital Nord, 42055, Saint-Étienne, France. 5. INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France. 6. Université Jean Monnet, Université de Lyon, Saint-Étienne, France. 7. Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, Saint-Étienne, France. 8. Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Étienne, France.
Abstract
OBJECTIVE: To quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers. METHODS: This was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40 mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8 h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach. RESULTS: The pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5 h post-dose and by 29% when administered 8 h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8 h post-dose. CONCLUSION: AC administration significantly reduces exposure to rivaroxaban even if AC is administered 8 h after rivaroxaban. These results suggest that AC could be used in rivaroxaban overdose and accidental ingestion to antagonise absorption. CLINICALTRIAL. GOV REGISTRATION NO: NCT02657512.
RCT Entities:
OBJECTIVE: To quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers. METHODS: This was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40 mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8 h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach. RESULTS: The pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5 h post-dose and by 29% when administered 8 h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8 h post-dose. CONCLUSION:AC administration significantly reduces exposure to rivaroxaban even if AC is administered 8 h after rivaroxaban. These results suggest that AC could be used in rivaroxabanoverdose and accidental ingestion to antagonise absorption. CLINICALTRIAL. GOV REGISTRATION NO: NCT02657512.
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