Lu Gaohua, Kim Crewe, Rachel Rose, Amin Rostami-Hodjegan, Karen Rowland Yeo, Masoud Jamei
Simcyp Limited (a Certara company)
Objectives: Dextromethorphan (DEX) is an in vitro and in vivo probe substrate for CYP2D6 that undergoes O-demethylation to dextrorphan (DOR) and N-demethylation to 3-mthoxymethorphinan (3MM). Both metabolites are then further metabolised to 3-hydroxymorphinan (3HM). In addition to CYP2D6, CYP3A4 and UGT2B7 are also involved in the elimination of DEX and its metabolites. In this study a PBPK model was developed for DEX and its 3 metabolites to explore the complex mechanism of drug-drug interaction (DDI) between DEX and rifampicin (RIF).
Methods: The Simcyp Simulator (V14R1) was used to build the PBPK model for each of the moieties. In particular, the elimination kinetics of the currently available DEX compound model in the Simulator were revised based on in vivo data for the major contributing enzyme CYP2D6 and in vitro data for the relative contributions of minor metabolic enzymes (including CYP2B6, 2C9, 2C18, 2C19 and 3A4). The DOR PBPK model was developed based on the clinical PK profiles after IV and oral dosing of DOR. Where relevant data were lacking, parameters relating to the parent were used for the PBPK models for 3MM and 3HM. The DEX model is linked to the 3 metabolite models via its elimination pathways. The performance of the PBPK model as a whole was verified using independent clinical data sets that had not been used in the model development. Sensitivity analysis was used to explore the potential for 2D6 induction by RIF.
Results: The whole PBPK model including DEX and its 3 metabolites was verified using various clinical studies in CYP2D6 EM and PM subjects, as well as DDI between DEX and quinidine. The observed DEX-RIF DDI could not be fully explained by induction of CYP3A4 alone (AUC Ratio=0.67 simulated vs. 0.27 observed [1]) and sensitivity analysis indicated that induction of CYP2D6 by RIF was required in order to recover the extent of clinical DDI.
Conclusions: The developed PBPK model was able to describe the complex kinetics of DEX and its 3 metabolites, as well as elucidate the mechanism of interaction between DEX and RIF. Although it is generally accepted that CYP2D6 is non-inducible the findings of the current study indicate that this may not be the case. Further studies are warranted to support this finding.
References:
[1] Kirby, B. J., A. C. Collier, et al. (2011). Drug Metab Dispos 39(12): 2329-2337.
Reference: PAGE 24 (2015) Abstr 3359 [www.page-meeting.org/?abstract=3359]
Poster: Drug/Disease modeling - Absorption & PBPK