Hannah Britz (1), Daniel Moj (1), Nina Hanke (1) and Thorsten Lehr (1)
(1) Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Objectives: Dronedarone is the strongest known perpetrator drug to evaluate the impact of P-gp inhibition on P-gp substrates (victim drugs) during co-administration[1]. Our objective was to establish a PBPK model of dronedarone to explore and predict the drug-drug interactions (DDIs) of dronedarone with P-gp substrates.
Methods: A PBPK model of dronedarone was built in PK-Sim® (version 6.0.3) and MoBi® (version 6.0.3). Drug-dependent parameters (e.g. logP, solubility) as well as concentration-time profiles (intravenous (iv) and oral (po) administration) and population data (e.g. age, weight) from clinical studies with dronedarone were obtained from literature. During model development, parameters, for which no information was available, were optimized to describe observed concentration-time profiles, followed by model evaluation (prediction of concentration-time profiles) and coupling of the dronedarone model with a previously developed digoxin model.
Results: Dronedarone inhibits its own metabolism through a mechanism-based inhibition (MBI) of CYP3A4. This MBI is extremely relevant for the description of the dronedarone PK after oral administration, because it leads to complete inhibition of CYP3A4 in the duodenal mucosa already at low doses of dronedarone. In contrast, the CYP3A4 MBI in the liver shows time- and dose-dependency. For simulation of the DDI the models of dronedarone and digoxin were coupled and a 1.26-fold increase of digoxin area under the curve (AUC) during dronedarone treatment was predicted. In clinical studies a 2.6-fold increase of digoxin AUC under dronedarone co-medication has been observed[2].
Conclusions: With the PBPK model of dronedarone the hypothesis of MBI as a relevant mechanism for the PK of dronedarone gets further support. To refine the prediction of the dronedarone-digoxin model, the PBPK model of dronedarone could be extended to include its main metabolite N-debutyldronedarone as an additional P-gp inhibitor.
References:
[1] U.S. Department of Health and Human Services, FDA, Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 2012.
[2] Kumi R, Garnett C, Gobburu J, Marroum P. Clinical Pharmacology and Biopharmaceutics Review – Application number: 22-425. 2006.
Reference: PAGE 25 (2016) Abstr 5830 [www.page-meeting.org/?abstract=5830]
Poster: Drug/Disease modeling - Absorption & PBPK