Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs . dextrorphan using quinidine inhibition

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Abstract
To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX. Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms. The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)). Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.