Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Delavenne X

PROVIDER: S-EPMC3703233 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Delavenne Xavier X Ollier Edouard E Basset Thierry T Bertoletti Laurent L Accassat Sandrine S Garcin Arnauld A Laporte Silvy S Zufferey Paul P Mismetti Patrick P

British journal of clinical pharmacology 20130701 1

<h4>Aim</h4>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.<h4>Methods</h4>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, o ...[more]

PMID: 23210726

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Project description:BackgroundAn agent-based modeling approach has been suggested as an alternative to traditional, equation-based modeling methods for describing oral drug absorption. It enables researchers to gain a better understanding of the pharmacokinetic (PK) mechanisms of a drug. This project demonstrates that a biomimetic agent-based model can adequately describe the absorption and disposition kinetics both of midazolam and clonazepam.MethodsAn agent-based biomimetic model, in silico drug absorption tract (ISDAT), was built to mimic oral drug absorption in humans. The model consisted of distinct spaces, membranes, and metabolic enzymes, and it was altogether representative of human physiology relating to oral drug absorption. Simulated experiments were run with the model, and the results were compared to the referent data from clinical equivalence trials. Acceptable similarity was verified by pre-specified criteria, which included 1) qualitative visual matching between the clinical and simulated concentration-time profiles, 2) quantitative similarity indices, namely, weighted root mean squared error (RMSE), and weighted mean absolute percentage error (MAPE) and 3) descriptive similarity which requires less than 25% difference between key PK parameters calculated by the clinical and the simulated concentration-time profiles. The model and its parameters were iteratively refined until all similarity criteria were met. Furthermore, simulated PK experiments were conducted to predict bioavailability (F). For better visualization, a graphical user interface for the model was developed and a video is available in Supporting Information.ResultsSimulation results satisfied all three levels of similarity criteria for both drugs. The weighted RMSE was 0.51 and 0.92, and the weighted MAPE was 5.99% and 8.43% for midazolam and clonazepam, respectively. Calculated PK parameter values, including area under the curve (AUC), peak plasma drug concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (Kel), terminal elimination half life (T1/2), apparent oral clearance (CL/F), and apparent volume of distribution (V/F), were reasonable compared to the referent values. The predicted absolute oral bioavailability (F) was 44% for midazolam (literature reported value, 31-72%) and 93% (literature reported value, ? 90%) for clonazepam.ConclusionThe ISDAT met all the pre-specified similarity criteria for both midazolam and clonazepam, and demonstrated its ability to describe absorption kinetics of both drugs. Therefore, the validated ISDAT can be a promising platform for further research into the use of similar in silico models for drug absorption kinetics.

Dataset Information

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

Publications

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

Similar Datasets

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