A.Blesius (1), S. Chabaud (1), M. Cucherat (1), P. Mismetti (2), JP. Boissel (1), P.Nony (1).
(1)Clinical Pharmacology Department, EA 643, Cardiovascular Hospital, Lyon, France; (2)University Hospital Bellevue, Saint-Etienne, France.
Objectives: In relation to their narrow therapeutic index, oral anticoagulant agents are often under prescribed, too low doses leading to thromboembolic events, and over-dosing being responsible for haemorrhagic complications. In the USA the proportion of treated patients with serious bleeding events is estimated at between 3 and 7.5% per year, and the annual percentage of related deaths is estimated to be 0.2%. On the other hand, the annual incidence of thromboembolic complications related to inadequate decoagulation is estimated at 5%. In order to better define the choice of oral anticoagulant agent and its dosage regimen in case of poor compliance, we performed an “in silico” study.
Methods: Six months therapy was simulated at steady-state in 30 patients for warfarin (W) and acenocoumarol (A), using five different profiles of poor compliance. The numerical simulation used widely described determinist PK-PD models of the two drugs [1,2,3] and generated consecutive dosing intervals in a stochastic way (truncated Gauss distribution, Markov regression process). Since drug non-compliance has many facets [4] (e.g. “drug holidays” or inappropriate and irregular dosing time), five profiles should illustrate these different patient behaviours. The numerical simulations were performed at an individual level, using Mathematica software and led to several INR parameter results illustrating INR features during time. The main endpoint was the time during which the INR values were found outside the target zone (< 2 and > 4.5).
Results: For a given profile of poor compliance simulated with a Markov regression model and supposing a once daily dose, the time duration (days) of an INR respectively > 4.5 was 18 + 15 for W and 12 + 8 for A (mean + 2SD). The duration of an INR and < 2 was 8 + 7.9 for W and 23 + 10 for A. Accordingly, supposing a twice daily dose, the corresponding time durations were 12 + 10 (W) and 0.7 + 1.7 (A) with an INR > 4.5, and 1 + 3 (W) and 6.2 + 5 (A) with an INR < 2.
Discussion: Intuitively, the long half-life of warfarin could damp the consequences of non-compliance on the efficacy and safety of the treatment in a more efficient way than acenocoumarol which has a short half-life. However our results indicate that physicians should take into consideration each individual patient’s compliance profile and the underlying disease (with its own thrombotic or haemorrhagic risks) for the choice of the most appropriate anticoagulant agent (including its daily regimen), in order to optimize the INR equilibrium and consequently to decrease the risk of adverse events.
References:
[1] Holford, N.H.G. ‘Clinical pharmacokinetics and pharmacodynamics of warfarin : understanding the dose-effect relationship.’ Clin Pharmacokinet 1986;11:483-504.
[2] Dayneka, N.L., Garg, V., Jusko, W.J. ‘Comparison of four basic models of indirect pharmacodynamic responses.’ J Pharmacokinet Biopharm 1993;21:457-78.
[3] Mismetti, P., Reynaud, J., Laporte-Simitsidis, S., Thijssen, H., Tardy-Poncet, B., Tardy, B., Buchmüller, A., Decousus, H. ‘Pharmacokinetic and pharmacodynamic variations of acenocoumarol orally administered either once or twice daily in patients with deep vein thrombosis.’ Fundam Clin Pharmacol 1998;12:631-635.
[4] Urquhart J. ‘Role of patient compliance in clinical pharmacokinetics : a review of recent research.’ Clin Pharmacokinet 1994;27:202-215.
[5] Boissel, J.P, Nony, P..’Using pharmacokinetic-pharmacodynamic relationships to predict the effect of poor compliance.’ Clin Pharmacokinet 2002;41:1-6.
Reference: PAGE 12 (2003) Abstr 371 [www.page-meeting.org/?abstract=371]
Poster: poster