Phenprocoumon Dose Requirements, Dose Stability and Time in Therapeutic Range in Elderly Patients With CYP2C9 and VKORC1 Polymorphisms

Katharina Luise Schneider; Melanie Kunst; Ann-Kristin Leuchs; Miriam Böhme; Klaus Weckbecker; Kathrin Kastenmüller; Markus Bleckwenn; Stefan Holdenrieder; Christoph Coch; Gunther Hartmann; Julia Carolin Stingl

doi:10.3389/fphar.2019.01620

Phenprocoumon Dose Requirements, Dose Stability and Time in Therapeutic Range in Elderly Patients With CYP2C9 and VKORC1 Polymorphisms

Front Pharmacol. 2020 Jan 28:10:1620. doi: 10.3389/fphar.2019.01620. eCollection 2019.

Authors

Affiliations

¹ Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
² Centre for Translational Medicine, Medical Faculty of the University of Bonn, Bonn, Germany.
³ Institute of General Practice, Medical Faculty of the University of Düsseldorf, Düsseldorf, Germany.
⁴ Institute of General Practice and Family Medicine, Medical Faculty of the University of Bonn, Bonn, Germany.
⁵ Institute of Laboratory Medicine, German Heart Centre Munich, Munich, Germany.
⁶ Institute of Clinical Chemistry and Clinical Pharmacology, Medical Faculty of the University of Bonn, Bonn, Germany.

Abstract

Background: Dose requirements of vitamin K antagonists are associated with CYP2C9 and VKORC1, but, compared to warfarin, less data is available about phenprocoumon. Furthermore, the effects on dose stability and anticoagulation quality are still unclear.

Methods: Aim was to scrutinize phenprocoumon dose requirements, dose stability and anticoagulation quality in association to CYP2C9 and VKORC1 in a natural cohort of elderly primary care patients. As a subgroup within the IDrug study, phenprocoumon treated patients with at least two INR values within three months before enrollment (n = 209) were analyzed concerning average weekly dose, standard deviation of weekly dose (intra-subject variability), constant dose (yes/no), average INR and TTR grouped by CYP2C9 and VKORC1 (and combinations).

Results: Average weekly dose per patient was 14.4 ± 5.3 mg, 11.9 ± 4.0 mg and 11.2 ± 4.3 mg in CYP2C9 wildtypes, *2 and *3 carriers (p < .0001) and 16.0 ± 4.2 mg, 13.3 ± 5.1 mg and 8.0 ± 2.7 mg per week in VKORC1 CC, CT and TT genotypes, respectively (p < .0001). Significant differences concerning intra-subject variability were detected among all groups (p < .0001) with the smallest variability in CYP2C9*3 carriers. TTR medians were 75.4%, 79.4% and 100% in wildtypes, *2 and *3 carriers, respectively (p = 0.0464). The proportion of patients with perfect control was highest among *3 carriers, but this result was not significant (p = 0.0713).

Discussion: Our analyses support the results of previous investigations regarding genotype-associated dose requirements and raise the hypothesis that dose stability and anticoagulation quality may be increased in CYP2C9*3 carriers. However, our data should be treated cautiously due to the small sample size.

Clinical trial registration: German Clinical Trials Register, identifier DRKS00006256.

Keywords: CYP2C9; VKORC1; dose; international normalized ratio; phenprocoumon; time in therapeutic range.