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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01620

DOI=10.3389/fphar.2019.01620

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Dose requirements of vitamin K antagonists are associated with <italic>CYP2C9</italic> and <italic>VKORC1</italic>, but, compared to warfarin, less data is available about phenprocoumon. Furthermore, the effects on dose stability and anticoagulation quality are still unclear.</p></sec><sec><title>Methods</title><p>Aim was to scrutinize phenprocoumon dose requirements, dose stability and anticoagulation quality in association to <italic>CYP2C9</italic> and <italic>VKORC1</italic> 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 <italic>CYP2C9</italic> and <italic>VKORC1</italic> (and combinations).</p></sec><sec><title>Results</title><p>Average weekly dose per patient was 14.4 ± 5.3 mg, 11.9 ± 4.0 mg and 11.2 ± 4.3 mg in <italic>CYP2C9</italic> wildtypes, <italic>*2</italic> and <italic>*3</italic> carriers (p &lt; .0001) and 16.0 ± 4.2 mg, 13.3 ± 5.1 mg and 8.0 ± 2.7 mg per week in <italic>VKORC1</italic> CC, CT and TT genotypes, respectively (p &lt; .0001). Significant differences concerning intra-subject variability were detected among all groups (p &lt; .0001) with the smallest variability in <italic>CYP2C9*3</italic> carriers. TTR medians were 75.4%, 79.4% and 100% in wildtypes, <italic>*2</italic> and <italic>*3</italic> carriers, respectively (p = 0.0464). The proportion of patients with perfect control was highest among <italic>*3</italic> carriers, but this result was not significant (p = 0.0713).</p></sec><sec><title>Discussion</title><p>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 <italic>CYP2C9*3</italic> carriers. However, our data should be treated cautiously due to the small sample size.</p></sec><sec><title>Clinical Trial Registration</title><p>German Clinical Trials Register, identifier DRKS00006256.</p></sec>