PMID- 26392328 OWN - NLM STAT- MEDLINE DCOM- 20161011 LR - 20220311 IS - 1472-8206 (Electronic) IS - 0767-3981 (Linking) VI - 29 IP - 6 DP - 2015 Dec TI - In vitro and in vivo evaluation of drug-drug interaction between dabigatran and proton pump inhibitors. PG - 604-14 LID - 10.1111/fcp.12154 [doi] AB - 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 Dabigatran plasma concentration and thrombin time were measured in blood samples withdrawn at 11 time points after each treatment.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. CI - (c) 2015 Societe Francaise de Pharmacologie et de Therapeutique. FAU - Ollier, Edouard AU - Ollier E AD - Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France. AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. AD - Universite Claude Bernard Lyon 1, Villeurbanne, F-69100, France. FAU - Hodin, Sophie AU - Hodin S AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. FAU - Basset, Thierry AU - Basset T AD - Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France. AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. FAU - Accassat, Sandrine AU - Accassat S AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. AD - Universite Jean Monnet, Universite de Lyon, Saint-Etienne, F-42023, France. AD - Unite de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, Saint Etienne, F-42055, France. FAU - Bertoletti, Laurent AU - Bertoletti L AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. AD - Universite Jean Monnet, Universite de Lyon, Saint-Etienne, F-42023, France. AD - Service de Medecine Therapeutique, CHU de Saint-Etienne, Saint-Etienne, F-42055, France. FAU - Mismetti, Patrick AU - Mismetti P AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. AD - Universite Jean Monnet, Universite de Lyon, Saint-Etienne, F-42023, France. AD - Service de Medecine Therapeutique, CHU de Saint-Etienne, Saint-Etienne, F-42055, France. FAU - Delavenne, Xavier AU - Delavenne X AD - Laboratoire de Pharmacologie Toxicologie, CHU Saint-Etienne, Saint-Etienne, F-42055, France. AD - Groupe de Recherche sur la Thrombose, EA3065, Universite de Saint-Etienne, Jean Monnet, Saint-Etienne, F-42023, France. AD - Universite Jean Monnet, Universite de Lyon, Saint-Etienne, F-42023, France. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20151007 PL - England TA - Fundam Clin Pharmacol JT - Fundamental & clinical pharmacology JID - 8710411 RN - 0 (2-Pyridinylmethylsulfinylbenzimidazoles) RN - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1) RN - 0 (Proton Pump Inhibitors) RN - 0K5C5T2QPG (Lansoprazole) RN - 32828355LL (Rabeprazole) RN - 83HN0GTJ6D (Cyclosporine) RN - D8TST4O562 (Pantoprazole) RN - EC 3.4.21.5 (Thrombin) RN - I0VM4M70GC (Dabigatran) RN - KG60484QX9 (Omeprazole) SB - IM MH - 2-Pyridinylmethylsulfinylbenzimidazoles/pharmacokinetics MH - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism MH - Adult MH - Caco-2 Cells MH - Cell Line, Tumor MH - Cyclosporine/pharmacokinetics MH - Dabigatran/*metabolism/*pharmacokinetics MH - Drug Interactions/*physiology MH - Humans MH - Lansoprazole/pharmacokinetics MH - Male MH - Omeprazole/pharmacokinetics MH - Pantoprazole MH - Proton Pump Inhibitors/*metabolism/*pharmacokinetics MH - Rabeprazole/pharmacokinetics MH - Thrombin/metabolism MH - Young Adult OTO - NOTNLM OT - bioavailability OT - caco-2 OT - dabigatran OT - omeprazole OT - pharmacokinetics OT - population model OT - proton pump inhibitors OT - rabeprazole EDAT- 2015/09/24 06:00 MHDA- 2016/10/12 06:00 CRDT- 2015/09/23 06:00 PHST- 2015/04/30 00:00 [received] PHST- 2015/09/01 00:00 [revised] PHST- 2015/09/10 00:00 [accepted] PHST- 2015/09/23 06:00 [entrez] PHST- 2015/09/24 06:00 [pubmed] PHST- 2016/10/12 06:00 [medline] AID - 10.1111/fcp.12154 [doi] PST - ppublish SO - Fundam Clin Pharmacol. 2015 Dec;29(6):604-14. doi: 10.1111/fcp.12154. Epub 2015 Oct 7.