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

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.

Adverse Drug Reactions in the Emergency Department: Is There a Role for Pharmacogenomic Profiles at Risk?—Results from the ADRED Study

“…A polymorphism in this subunit of VKORC1 was known to lead to a higher sensitivity for VKA [39]. The CYP2C9 and the VKORC1 polymorphism might both influence dose stability and anticoagulation quality in phenprocoumon users [40]. While CYP2C9 is the major enzyme for the metabolism of warfarin, the VKA phenprocoumon used here was also metabolized by CYP3A4, which exposed it to many potential drug-drug or drug-food interactions.…”

Longitudinal analysis of safety and medication adherence of patients in the Fingolimod patient support program: a real-world observational study

“…Implementation is defined as “the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose is taken” 8 . Implementation on day D is the probability of taking (at least) all prescribed doses on day D for a subject who is still persistent on that day 9 . Persistence is the time between initiation and discontinuation of the treatment 8 .…”

“…Persistence is the time between initiation and discontinuation of the treatment 8 . Persistence on day D is the probability of not yet having discontinued on day D 9 . Discontinuation is either a unilateral patient decision or a physician–patient joint decision (e.g., AEs, ineffectiveness or pregnancy).…”

“…Discontinuation is either a unilateral patient decision or a physician–patient joint decision (e.g., AEs, ineffectiveness or pregnancy). Adherence on day D is the probability of taking at least all prescribed doses on day D (for a patient who entered the F-PSP) 9 . Implementation and persistence were modelled longitudinally using EM data.…”

“…Persistence was represented by a Kaplan–Meier curve, which estimates the probability of being persistent on each day D, taking into account censoring durations. Adherence was calculated on each day D as the product between implementation and persistence, representing the probability of taking at least the prescribed dose on day D 9 .…”