Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers

Dextromethorphan (DM) pharmacological properties predict that the widely used cough suppressant could be used to treat several neuronal disorders, but it is rapidly metabolized after oral dosing. To find out whether quinidine (Q), a CYP2D6 inhibitor, could elevate and prolong DM plasma profiles, 2 multiple-dose studies identified the lowest oral dose of Q that could be used in a fixed combination with 3 doses of DM. A multiple-dose study in healthy subjects with an extensive ora poor enzyme metabolizer phenotype evaluated the safety and pharmacokinetic profile of a selected fixed-dose combination (AVP-923). Study 1 randomized 46 healthy subjects, who were extensive CYP2D6 metabolizers, to receive 0, 2.5,10, 25, 50, or 75 mg Q twice daily in combination with 30 mg DM for 7 days. Plasma and urine samples were collected after the first and last doses for the assay of DM, dextrorphan (DX) and Q. Study 2 randomized 65 healthy extensive CYP2D6 metabolizers to 8 groups given twice-daily 45- or 60-mg DM doses combined with 0, 30, 45, or 60 mg Q for 7 days. The effects of increasing Q were not different with doses greater than 25 mg, whereas lower doses showed a dose-related increase in plasma DM concentrations. Urinary ratios of DM/DX showed a Q dose- and time-related increase in then umber of subjects converted to the poor metabolizer phenotype that reached 100% on day 3 of dosing with 25 mg Q. Results from both studies indicated that 25 to 30 mg Q is adequate to maximally suppress O-demethylation of DM. Study 3 evaluated 7 extensive metabolizers and 2 poor metabolizers given an oral capsule every 12 hours containing 30 mg Q combined with 30 mg DM. DM plasma AUC values increased in both groups of subjects during the 8-day study. The mean urinary metabolic ratio (DM/DX) increased at least 27-fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers. Safety evaluations, including electrocardiograms, indicated that the combination was well tolerated, with no difference between extensive and poor metabolizer phenotypes.