2010 - Berlin - Germany

PAGE 2010: Methodology- Model evaluation
Julie Grenier

Population Pharmacokinetic Meta Analysis: Inhibition by Quinidine of the First-Pass and Systemic Metabolism of Dextromethorphan to Dextrorphan

J. Grenier(1), JR. Lavigne(1), LE. Pope(2)

(1) Clinical Pharmacology Department, Celerion, Montrťal, Qc, Canada; (2) Avanir Pharmaceuticals, Aliso Viejo, CA, USA.

Objectives: Zenvia is a combination product of Dextromethorphan (DM) and Quinidine (Q) where Q is used as an inhibitor of DM metabolism by CYP2D6 enzymes. The objectives of this study were to determine the population pharmacokinetic (PK) parameters of Q, DM and its metabolite dextrorphan (DX) in plasma after single and multiple doses of Zenvia and to identify the impact of demographic covariates on the population PK parameter estimates.

Methods: The results from a series of Phase I - III studies were pooled. Data from 133 subjects were analyzed using a total of 5730 data points for Q, DM and DX combined. The impact of covariates was assessed graphically. First, Q data were modeled and resulting PK parameters were then fixed for each individual so that predicted Q concentrations were used for the modeling of DM and DX plasma data with inhibition by Q of the metabolic conversion of DM to DX. Standardized visual predictive checks (SVPC) were evaluated for the internal and external validation of the final population PK models.1 A set of 70 subjects from other studies were used for the external validation.

Results: The population PK model that best described the PK of Q in plasma was a 2-compartment model with linear absorption and elimination and a lag time for absorption. The population PK model that best described the PK of DM and DX in plasma was a model with 2 first-order constants of absorption with lag times, 2 compartments for DM and 1 compartment for DX. The metabolic conversion of DM to DX was described by a sigmoidal inhibition model related to Q concentrations, both at first-pass and systemically. The model discrimination and selection for DM/DX was based on data from extensive-metabolizers (EM) only. A maximum a posteriori Bayesian (MAPB) analyses was performed on data from one of the studies where there was an intermediate metabolizer (IM) and an ultra-metabolizer (UM). The model was adequate to fit these 2 subjects. A clear difference was seen in the inhibition curves between the different genotypes.

Conclusions: The PK of Q, DM and DX are well described by the population PK model developed. None of the available covariates were considered significantly correlated with any of the PK parameters. The external validation results show that the model predicts well the plasma PK of Q, DM and DX and can be used for the MAPB analysis of other sets of data or to predict the outcome of different dosing regimens for future clinical use.

[1] Wang D, Standardized Visual Predictive Check in Model Evaluation - Methodology and Applications.  PAGE 18 (2009) Abstr 1501 [www.page-meeting.org/?abstract=1501]

Reference: PAGE 19 (2010) Abstr 1757 [www.page-meeting.org/?abstract=1757]
Poster: Methodology- Model evaluation
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