title: In vitro and in vivo evaluation of drug-drug interaction between dabigatran and proton pump inhibitors.
abstract: To quantify the drug-drug interactions between dabigatran etexilate (DE) and proton pump inhibitors (PPI) and in particular the role of P-gp activity modulation. In the first part of the study, efflux ratios of DE were evaluated using the caco-2 cell line in the presence of pantoprazole, omeprazole, rabeprazole, lansoprazole and ciclosporin A (positive control). The two PPI that reduced the efflux ratio of dabigatran to the greatest and least extent, respectively, were used during the second part of the study, comprising a single-centre, randomised, open-label study with an incomplete Latin square design. Nine healthy volunteers received DE (150 mg) alone, DE (150 mg) with the first PPI and DE (150 mg) with the second PPI in randomised sequence. Dabigatran plasma concentration and thrombin time were measured in blood samples withdrawn at 11 time points after each treatment. Models were built using a nonlinear mixed-effect modelling approach. Omeprazole and rabeprazole were the two PPI that reduced the efflux ratio of DE least and most, respectively. The PK model was based on an inverse Gaussian absorption process with one compartment. The relationship between dabigatran concentration and thrombin time was considered linear. Some PK profiles had dramatically low concentration values due to poor absorption. These profiles were clustered using a between subject model mixture with interoccasion variability. The concomitant administration of PPI did not significantly change dabigatran pharmacokinetics. DE is subject to high absorption variability, precluding evaluation of the effect of PPI on its pharmacokinetics.
authors.affiliation: Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France.|Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.|Université Claude Bernard Lyon 1, Villeurbanne, F-69100, France.
authors.forename: Edouard
authors.initials: E
authors.lastname: Ollier
authors.affiliation: Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hodin
authors.affiliation: Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France.|Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Basset
authors.affiliation: Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.|Université Jean Monnet, Université de Lyon, Saint-Etienne, F-42023, France.|Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, Saint Etienne, F-42055, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Accassat
authors.affiliation: Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.|Université Jean Monnet, Université de Lyon, Saint-Etienne, F-42023, France.|Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Etienne, F-42055, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bertoletti
authors.affiliation: Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.|Université Jean Monnet, Université de Lyon, Saint-Etienne, F-42023, France.|Service de Médecine Thérapeutique, CHU de Saint-Etienne, Saint-Etienne, F-42055, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mismetti
authors.affiliation: Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France.|Groupe de Recherche sur la Thrombose, EA3065, Université de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France.|Université Jean Monnet, Université de Lyon, Saint-Etienne, F-42023, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Delavenne
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000493:pharmacokinetics; D000069604:Dabigatran / Q000378:metabolism* / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology*; D006801:Humans; D064747:Lansoprazole / Q000493:pharmacokinetics; D008297:Male; D009853:Omeprazole / Q000493:pharmacokinetics; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D064750:Rabeprazole / Q000493:pharmacokinetics; D013917:Thrombin / Q000378:metabolism; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D016572:Cyclosporine; D000077402:Pantoprazole; D013917:Thrombin; D000069604:Dabigatran; D009853:Omeprazole
keywords: bioavailability; caco-2; dabigatran; omeprazole; pharmacokinetics; population model; proton pump inhibitors; rabeprazole