The use of an indirect response model to assess interaction between drugs: acenocoumarol and amoxicillin + clavulanic acid
X Delavenne (1), T Basset (2), P Girard (3) , H Decousus (1,4), P Mismetti (1,4), S Laporte (1)
(1) Department of clinical pharmacology, EA3065, Saint-Etienne University Hospital, France;(2) Laboratory of pharmacology and toxicology, Saint-Etienne University Hospital, France; (3) EA3738, Faculté de Médecine de Lyon Sud, Oullins, France;(4) Department of Internal medicine and therapeutics, EA3065, Saint-Etienne University Hospital, France
Objectives: It has been reported in the literature an increase of anticoagulation level, assessed by prothrombin time, when acenocoumarol, an oral antivitamin K, is associated with amoxicillin plus clavulanic acid (antibiotic drug). The aim of present study was to investigate quantitatively the influence of amoxicillin plus clavulanic acid on pharmacokinetic (PK) and pharmacodynamic (PD) of acenocoumarol.
Methods: A single dose of 8 mg of acenocoumarol were orally administered to 8 healthy volunteers on day 1 and 8. From day 3 to 9, the volunteers received 1g of amoxicillin + 250 mg of clavulanic acid. Eleven blood samples were collected at day 1 and at day 8 for each volunteer; plasma concentrations of acenocoumarol and prothrombin time ratio (PTr) were measured. The PK-PD analysis was performed with a non-linear mixed effect model in NONMEM using FOCE INTERACTION method. In a first step, the structural PK model was identified by pooling the present dataset with other individual data from PK acénocoumarol trials. In a second step, an indirect PK-PD model was build conditional on the individual Bayesian PK parameter estimations from first step; PTr was fitted to an indirect action model with inhibition of the response synthesis as described by Dayneka . The model is composed of two functions, one for the clotting factor (CF) and one for PTr: dCF/dt = Kin*(1-(Cp/(Cp+C50))) – Kout*CF PTr = PTr0*CF/(θ+CF), CF are the clotting factors, θ is the hyperbolic parameter. Demographic covariates, as well as antibiotic treatment effect, were tested on PK and PD parameters. The model was validated by visual predictive check.
Results: Plasma concentrations of acenocoumarol were best fitted with a two compartment and first-order absorption model. Weight was included as covariate on V2 and antibiotic treatment effect on CL, thus reducing unexplained inter-individual variabilities from 10.0% to 0.3% for V2 and from 12.2% to 8.7% for CL. A significant 15% decrease in anecocoumarol clearance was observed when antibiotic was prescribed. PTr levels were well fitted by the indirect response model, but no significant covariate were identified, and especially the co-administration of antibiotic did not induce any significant changes on the prothrombin time.
Conclusions: To our best knowledge, this is the first application of an indirect response model to acenocoumarol data for assessing drug interaction. The only drug interaction with antibiotic that was found in this study was at the PK level, but not at PD level. Despite some case reports of clinical suspicions, amoxicillin plus clavulanic acid do not seem to affect the pharmacodynamic activity of acenocoumarol as assessed by prothrombin time.
 J Pharmacokinet Biopharm 1993; 21: 457-78.