Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters.
OBJECTIVE
The anticoagulation response to vitamin K antagonists is characterised by high inter-individual variability. The impact of single nucleotide polymorphisms (SNPs) in several genes of enzymes involved in the vitamin K cycle on phenprocoumon dose variability and phenprocoumon plasma concentrations is still under investigation.


METHODS
We assessed the influence of VKORC1 c.-1639G>A, CYP2C9*2, CYP2C9*3, CYP4F2 c.1297G>A, CALU c.*4A>G, EPHX1 c.337T>C, GGCX c.214+597G>A, F7 c.-402G>A, F7 c.-401G>T, PROC c.-228C>T and PROC c.-215G>A along with clinical and demographic parameters on steady-state phenprocoumon therapy in 75 patients. A prediction model was developed for total phenprocoumon plasma concentrations and daily phenprocoumon doses required for therapeutic anticoagulation.


RESULTS
The VKORC1 c.-1639 genotype was the main predictor of the phenprocoumon daily dose (adjusted R(2) = 37.6%) and the total phenprocoumon concentration (adjusted R(2) = 38.3%). CYP2C9 affected the phenprocoumon concentration, but not the dose requirements. SNPs in the other genes of the vitamin K cycle, concomitant medication, nicotine use and alcohol consumption did not predict phenprocoumon concentrations and phenprocoumon dose requirements in a multiple linear regression model. Phenprocoumon concentrations were predicted by VKORC1 c.-1639, CYP2C9 genotype, age and BMI. The final prediction model for the daily phenprocoumon dose requirements comprised VKORC1 c.-1639 genotype, age and height accounting for 48.6% of the inter-individual variability.


CONCLUSIONS
A rough prediction of phenprocoumon maintenance doses can be achieved by a limited set of parameters (VKORC1, age, height). The investigated SNPs in CYP4F2, CALU, EPHX1, GGCX, F7, and PROC did not improve the predictive value of a pharmacogenetic-based dosing equation for phenprocoumon.
German Red Cross, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany.
Christof
C
Geisen
German Red Cross, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany.|Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, Frankfurt, Germany.
Beate
B
Luxembourg
Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
Matthias
M
Watzka
Institute of Legal Medicine, University Hospital Frankfurt, Frankfurt, Germany.
Stefan W
SW
Toennes
German Red Cross, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany.
Katja
K
Sittinger
Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.
Milka
M
Marinova
Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany.
Nicolas
N
von Ahsen
Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, Frankfurt, Germany.
Edelgard
E
Lindhoff-Last
German Red Cross, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany.
Erhard
E
Seifried
German Red Cross, Institute of Transfusion Medicine and Immunohaematology, University Hospital Frankfurt, Frankfurt, Germany. johannes.oldenburg@ukb.uni-bonn.de.|Institute of Experimental Haematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany. johannes.oldenburg@ukb.uni-bonn.de.|Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany. johannes.oldenburg@ukb.uni-bonn.de.
Johannes
J
Oldenburg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001779:Blood Coagulation Factors / Q000235:genetics*; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D010644:Phenprocoumon / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D014812:Vitamin K / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D014812:Vitamin K; D010644:Phenprocoumon