Pharmacokinetic and Pharmacodynamic Variability of Fluindione in Octogenarians

Abstract

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

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

“…Complementary data were recently obtained in a cohort of 131 octogenarians initiating fluindione with an INR target greater than 3.0 in 60% of them: sex, body weight, and prior amiodarone therapy influenced pharmacokinetic parameters, whereas the only factors influencing pharmacodynamic parameters were prior surgery and paroxetine therapy (20). However, in contrast to our study, this study did not provide data regarding the fluindione dose requirement variability since most patients did not remain in the study long enough to reach a stable INR (20).…”

“…In middleaged adults (target INR 2.5), a mean daily dose requirement of 22 mg, ranging from 5 to 40 mg (15) has been reported, indicating substantial inter-individual variability in the dose requirement (13,(15)(16)(17)(18)(19). A few studies conducted in different settings have focused on the pharmacokinetic/pharmacodynamic (PK/PD) response to fluindione, mainly at the start of treatment (13,17,19,20). However, neither the mean dose requirement in elderly patients nor factors contributing to the dose variability in this age group are known.…”