A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin

Abstract

Aim: The aim of this study was to develop a PK/PD model to assess drug-drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.

Methods: Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.

Results: The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively.

Conclusion: The model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin.

Figure 1

Absorption rate of dabigatran with and without clarithromycin. The solid black line represents the median absorption rate of dabigatran without clarithromycin (A) and with clarithromycin (B). The dashed lines indicate the 5% and 95% percentiles

Figure 2

Visual predictive check. The envelope indicates the 90% confidence interval of simulations. The grey circles represent data obtained without clarithromycin. The white circles represent data obtained with clarithromycin

Figure 3

Pharmacokinetic profiles of three volunteers. Fit of dabigatran plasma concentration with (solid line) and without (dashed line) clarithromycin. Grey circles represent data obtained without clarithromycin. White circles represent data obtained with clarithromycin