In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the response to fluindione, an oral anticoagulant drug, in a general population of octogenarians inpatients.

Measurements of fluindione concentrations and INR (International Normalised Ratio) were obtained from 131 inpatients initiating fluindione treatment. Treatment was adjusted according to routine clinical practice. The data was analysed using non-linear mixed effect models, and the parameters were estimated using MONOLIX 3.2.

The pharmacokinetics of fluindione was monocompartmental, while the evolution of INR was modelled according to a turnover model (inhibition of vitamin K recycling). Interindividual variability was very large. Clearance decreased with age and with prior administration of cordarone. Patients who underwent surgery before the study had lower IC₅₀, leading to an increased sensitivity to fluindione.

Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

Evidence-based clinical practice guidelines recommend vitamin K antagonists in the prevention of stroke in atrial fibrillation [1, 2], in the treatment of venous thromboembolism [3], in patients with mechanical valve and in the first 3 months following bioprotheses implantation [4]. Despite their proven benefit, studies attest to their underutilisation particularly among elderly individuals [5, 6]. Antivitamin K agents (AVK) act by inhibiting the reduction reactions by which the vitamin K is recycled, in turn decreasing the synthesis of vitamine K-dependent coagulation factors (factors II (prothrombin), VII, IX, X, protein C, and protein S) [7]. The two main classes are coumarin derivatives, including warfarin and acenocoumarol, and indanedione derivatives, including fluindione and phenindione. Fluindione constitutes about 80% of AVK prescriptions in France [8].

AVK are characterised by a large between-, but also within-patient variability in the dose-response relationship. The therapeutic window is narrow, so that clinicians must walk a thin line between suboptimal dosage risking thromboembolic events and higher doses potentially risking bleeding episodes. The frequency and seriousness of haemorragic adverse events varies in the literature, depending on the population, the prescribed therapeutic range, the other treatments co-administered and the duration of treatment with AVK [9]. The Adverse Event Reporting system of the US Food and Drug Administration provides evidence that warfarin is among the top 10 drugs with the greatest number of serious adverse events. In France, where the present study was performed, iatrogenic events due to oral anticoagulant drugs represent the first cause of hospital admission for drug-related adverse event [10], totalling about 17000 admissions a year, and an estimated 3000 to 5000 deaths [11]. A meta-analysis of available clinical trials in patients anticoagulated for venous thromboembolism, reported a case-fatality rate of major bleeding of 13.4% in all patients (95% confidence interval 9.4 to 17.4%) [12]. Haemorragic events are overall more frequent and more severe in elderly patients compared to the general population [13]. The contribution of age per se to this increased risk is somewhat controversial, some studies pointing to an increase of the incidence of haemorragic events as a function of age [9] while others do not find it significant [14], but the fact that severity increases with age is undisputed [15] so that scores developed to predict the risk of bleeding include age over 65 as an independent risk factor [2, 16]. The main risk factors known to bring about haemorragic complications are level of anticoagulation, poor quality of monitoring, lack of patient eduction, associated comorbidities and comedications, including interactions with drugs interfering with haemostasis, and being in the first months of treatment [9, 14, 17]. Variability in International Normalised Ratio (INR) levels is also higher in elderly patients [18, 19]. A large part of this variability can be explained by changes in the dose-concentration relationship (pharmacokinetics, PK), or in the concentration-response relationship (pharmacodynamics, PD). Measurement of AVK concentrations can contribute to a better understanding of these two components by separating these two contributions.

In the present paper, we describe the findings from the PREPA study, investigating the pharmacokinetics and pharmacodynamics of fluindione in octogenarians using non-linear mixed effect models. The primary objective of PREPA was to study the factors influencing the source of variability in the response to fluindione in elderly inpatients starting fluindione, with a special interest in comorbidities and comedications.

Fluindione is an AVK used mostly in France, where it is regarded as an interesting alternative to the warfarin; contrary to warfarin, fluindione is not a racemic mixture and its longer half-life is considered to help stabilise INR levels [24]. As other anticoagulant drugs however, it is a difficult drug to adjust. In a previous study called ADAP, we investigated the pharmacokinetics and pharmacodynamics of fluindione in a general population of patients initiating treatment [25, 26]. In these younger patients (mean 60 years, range 29–89), we demonstrated not only large IIV, but also, through a follow-up study recording dose changes and evolution of anticoagulation after discharge from the hospital, a sizeable intraindividual variability. This variability led to fluctuations in the anticoagulation level even in patients thought to be stabilised when leaving the hospital [27].

In the present study, we used a PK/PD model closely related to the one developed in ADAP. The main differences are the absorption model, which was previously assumed to a bolus dose and which we fixed here, and the use of a Hill model to represent drug effect. The estimates of CL and V were very close to the value estimated assuming an IV bolus, but the statistical criterion was slightly better with an oral absorption phase. The estimates of the PK parameters however are quite different from previously [25, 26]. In the final model, V was estimated to be around 8 L, while CL was 0.1 L.hr⁻¹. In the ADAP study on the other hand, we estimated these parameters to be respectively 37 L and 0.49 L.hr⁻¹. Both sets of parameters however give the same estimate for half-life, 56 h versus 52 h previously. The increased exposure was also apparent in the measured concentrations: in the ADAP study, subjects received daily doses of fluindione, with starting doses of 15 to 20 mg, and concentrations after 5 days of treatment were around 0.8 to 1.2 mg.L⁻¹, while in PREPA concentrations at day 5 range from 1 to over 8 mg.L⁻¹ as shown in figures 1 and 4. In addition, starting doses were lower, most patients receiving 10 mg initially or less. Thus, compared to the previous study, we observe a marked increase in the exposure to fluindione. Since fluindione is administered orally, the reported V and CL are apparent parameters, so an explanation to this discrepancy with previous results is a difference in bioavailability between the two studies. However, this would require a more than four-fold increase in bioavailability in elderly patients compared to the younger population previously studied. Fluindione is to some extent cleared by the liver, with the hepatic metabolism of fluindione appearing to be mediated by CYP2C9 [28], but is mainly renally excreted, so that we do not expect first-pass effect to be a major determinant of drug concentrations; the increase in drug exposure would then be driven by a dramatic increase in the absorption process. Changes in plasma protein binding could be another possibility. For all drugs eliminated primarily by the liver total exposure is independent of protein binding but, like fluindione, oral drugs eliminated by nonhepatic high extraction ratio routes exhibit changes in unbound drug exposure when protein binding changes. This would not be expected to affect exposure to such an extent since fluindione does not exhibit a particularly high extraction ratio [29]. The smaller volume of distribution might be the consequence of the combination of a lowered volume of tissue with an increase of the fraction unbound in tissue (V=V_p + V_t f_u /f_ut ), both clinically relevant in an elderly population with a lipophilic drug [30]. Modification, either increase or decrease, of transit times in this heavily medicated population could also explain an increase in the fraction absorbed by changing the dissolution of fluindione; indeed, 117 patients (89%) received drugs modifying transit, and slower intestinal transit times are frequently observed in the elderly. The alteration in PK exposure could therefore be due to a combination of factors [30] and warrants further exploration in a controlled study.

Dose reduction with age is also observed for other oral anticoagulants [18, 24]. The latter study, although admittedly retrospective, included over 22 000 patients, and found that patients aged 80 years or older required doses one-third to one-half of those given to patients younger than 50. For fluindione, Mahé et al. observed in a retrospective study that patients over 75 years old required a lower dose of fluindione than younger patients for a comparable INR [31], which can be interpreted as due to modifications in exposure in the light of our results. For the PD parameters, we found an estimate of IC₅₀ about 60% higher than in the ADAP study (2.18 mg.L⁻¹ instead of 1.35 mg.L⁻¹), but still within the same range, suggesting that elderly patients have a similar sensitivity to fluindione despite having an increased exposure. The present study provides a rationale explaining the findings of others that lower doses are required in elderly patients, by linking them to PK, and underscores the importance of having both PK and PD measurements in order to separate pharmacokinetic and pharmacodynamic changes. k_out on the other hand was noticeably smaller (0.03 versus 0.18 hr⁻¹), indicating a slower turnover than in younger patients.

We used the model and parameter estimates to predict a dose that should be given in order to maintain an INR within the therapeutic range at steady-state. Consistent with the observation that the concentrations were higher in this population of elderly patients than in the population we previously studied [25, 26], the model predicted relatively low doses, suggesting a daily 10 mg dose, or an alternance of 5 and 10 mg doses, should be a safe starting dose for most patients. This is also in line with the maintenance doses observed in the retrospective study by Mahé [31]. Fluindione however is still packaged as 20 mg pills, which are in practice difficult to divide for routine treatment.

The present study was targeted towards elderly patients during hospitalisation, since this population is both more likely to receive anticoagulant drugs and more fragile, being often polymedicated and with comorbidities. These patients are therefore more susceptible to bleeding and dose adjustment for oral anticoagulants is particularly difficult [32]. Given its observational nature and the short duration, the PREPA study was not specifically designed to investigate risk factors for clotting or bleeding; a more detailed analysis of the 8 bleeding events which occurred in the subset of patients with atrial fibrillation can be found in [20]. A major objective of the present study was to identify covariates that could explain some of the variability in the response. We found the pharmacokinetic parameters to be influenced by gender, weight and age, as well as prior administration of cordarone (amiodarone) while the only covariates influencing pharmacodynamic parameters were prior surgery and administration of deroxat. We did not find any relationship with time-varying comedications, but this may be due to the heterogeneity of the population and to the small sample size. Cordarone has been reported to increase the haemorragic risk [33], which could relate to the 20% reduction we find, translating into an increased exposure. We did not find a relationship with anti-infective agents (antibiotics and anti-fungal drugs) as in that study; nearly half of the patients received an antibiotic at some point during treatment, but it is possible that the analysis could not pick up a relationship especially if the influence is delayed, since we considered only an on/off type of relationship. Also the sample size was too small to consider each drug separately so we pooled the different antibiotics and the different dosages for the analyses. About a third of the patients took part in the optional pharmacogenetic study. We found no relationship between the 3 genetic polymorphisms and PK or PD parameters. The influence of CYP2C9 on PK through metabolism has been described for warfarin [34]; for fluindione, a recent study in healthy volunteers showed a lower clearance in carriers of the *3 allele [28], while the influence on the response is expected to be related to VKORC1 [35, 28]. We were not able to confirm these relationships here, perhaps due to the small number of subjects.

Most patients did not remain in the study long enough to reach a stable INR. However, even within the duration of their stay, we noted that dose changes occurred too often and sometimes irrationally. In particular, the long time-course of INR evolution after AVK did not appear well anticipated by the prescribing clinicians. This is apparently partly due to a lack of follow-up, as doses are frequently modified based only on the latest INR, without considering the pattern of doses given and INRs measured since the beginning of the treatment. In several countries specialised anticoagulation clinics have been set up to help manage anti-vitamin K drugs and have been shown to improve management of anticoagulation treatment [8]; a pilot clinic now exists in France [36]. A perspective of the present work could be to develop a software helping clinicians to anticipate the future evolution of anticoagulation, by producing plots based on individual INR measurements and dosing regimen [37, 38].

In conclusion, the PREPA observational study highlighted that dose adjustement for AVK agents is still a major issue, especially in the elderly. The complexity of INR dynamics and the resulting delay between the time-course of the drug and the clinical variations of anticoagulation levels make it difficult to anticipate changes in INR, so that adjustements in doses must be made after taking into account the evolution over several days and not a single measurement. Elderly patients should be treated as a special population presenting a noticeably increased pharmacokinetic exposure to the drug. They should receive significantly lower doses and the onset of treatment should remain conservative.