Study of the Digoxin-Acenocoumarol Interaction in Patients using Population Pharmacokinetics
Lanao JM, Atencio DR, Martín-Suárez A, Méndez ME*, López FG, Zarzuelo A
Department of Pharmacy and Pharmaceutical Technology. Faculty of Pharmacy. University of Salamanca. Spain; *Pharmacy Service. Rio Hortega Hospital. Valladolid. Spain.
The objective of the study has been to evaluate the interaction between Digoxin and Acenocoumarol using population pharmacokinetics. The study was conducted in 60 outpatients on Digoxin therapy attending the Pharmacy Service for routine monitoring of their Digoxin serum levels. The patients were distributed in two groups: Group I (n=14): patients on Digoxin therapy; Group II (n=46): patients on joint treatment with Digoxin and Acenocoumarol. The population parameters of fixed and random effects has been estimated using a fixed effects modeling, by the NONMEM program. Being a structural basic model, a one-compartment model with first-order elimination was used, fitting the minimum serum concentrations at the steady-state. The selected error models were proportional for the interindividual variability and the additive for the residual variability. The analyzed covariate was the concomitant treatment with Acenocoumarol (ACN) that was considered like a categoric covariate (yes/no). The Digoxin level/dose ratio established in the patients of Group II was significantly lower (p<0.01) that obtained in the Group I. The value of the objective function presented a statistically significant reduction when the covariate ACN was introduced in estimation of the serum clearance (p<0.01) and in the apparent distribution volume (p<0.05).
FINAL MODEL SELECTED:
CLp(ml/min/Kg)=1.33*(1+0.80 *ACN)
Vd(1/Kg)=10.91
VARIABILITY:
CLp(CV%)=25.43
Vd(CV%)=38.60
Residual (CV%)=8.43%
The concomitant administration of Digoxin and Acenocoumarol supposes a populational increment of 80% in the value of the serum clearance though submitted to certain interindividual variability. The results obtained in this study demonstrate the existence of an interaction between Digoxin and Acenocoumarol at elimination level with a certain degree of influence in the distribution of drug. The reduction of the serum levels of Digoxin in patients treated with Acenocoumarol, would make necessary an increment in the doses of the drug that should be clinically evaluated.