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Thromb Haemost 2014; 111(04): 705-712
DOI: 10.1160/TH13-07-0555
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

A model predicting fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone

Caroline Moreau
1   Sorbonne Paris Cité, INSERM UMR-S-775, Université Paris Descartes, Paris, France
2   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie UF Pharmacogénétique et Oncologie Moléculaire, Paris, France
3   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Hématologie Biologique, Paris, France
,
Eric Pautas
4   Assistance Publique Hôpitaux de Paris, Hôpital Charles Foix, Service de Gériatrie, Ivry-sur-Seine, France
5   Sorbonne Paris Cité, INSERM UMR-S-765, Université Paris Descartes, Paris, France
,
Charlotte Duverlie
3   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Hématologie Biologique, Paris, France
,
Celia Berndt
1   Sorbonne Paris Cité, INSERM UMR-S-775, Université Paris Descartes, Paris, France
5   Sorbonne Paris Cité, INSERM UMR-S-765, Université Paris Descartes, Paris, France
,
Marion Andro
6   CHRU de Brest, Service de Médecine Interne-Gériatrie, Brest, France
,
Isabelle Mahé
7   Assistance Publique Hôpitaux de Paris, Hôpital Louis Mourier, Service de Médecine Interne, Colombes, France
,
Joseph Emmerich
5   Sorbonne Paris Cité, INSERM UMR-S-765, Université Paris Descartes, Paris, France
8   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Médecine Vasculaire, Paris, France
,
Karine Lacut
9   EA3878, Université de Bretagne Occidentale – Inserm, Centre d’Investigation Clinique CIC 0502, Brest France
,
Grégoire Le Gal
9   EA3878, Université de Bretagne Occidentale – Inserm, Centre d’Investigation Clinique CIC 0502, Brest France
,
Isabelle Peyron
10   Assistance Publique Hôpitaux de Paris, Hôpital Charles Foix, Pharmacie, Ivry-sur-Seine, France
,
Isabelle Gouin-Thibault
5   Sorbonne Paris Cité, INSERM UMR-S-765, Université Paris Descartes, Paris, France
11   Assistance Publique Hôpitaux de Paris, Hôpital Cochin-Hôtel-Dieu, Service d’Hématologie Biologique, Paris, France
,
Jean-Louis Golmard
12   Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Biostatistiques, Paris, France
,
Marie-Anne Loriot
1   Sorbonne Paris Cité, INSERM UMR-S-775, Université Paris Descartes, Paris, France
,
Virginie Siguret
3   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Hématologie Biologique, Paris, France
5   Sorbonne Paris Cité, INSERM UMR-S-765, Université Paris Descartes, Paris, France
› Author Affiliations
Further Information

Publication History

Received: 11 July 2013

Accepted after major revision: 16 November 2013

Publication Date:
29 November 2017 (online)

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Summary

Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0–3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74). Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e. the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1,CYP4F2,ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

Keywords

Vitamin K antagonist - fluindione - VKORC1 - model - elderly

 

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