• Ram P Kapil, Kristen Friedman, Alessandra Cipriano, Gregory Michels, Manjunath Shet, Sabiha A Mondal, and Stephen C Harris.
• Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut. Electronic address: Ram.Kapil@pharma.com.
• Clin Ther. 2015 Oct 1; 37 (10): 2286-96.

PurposeA single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite. This study examined the influence of the coadministration of paroxetine, a strong selective CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone (and hydromorphone) in healthy adults.MethodsIn this randomized, double-blind, 2-period, 2-treatment crossover study, 24 healthy subjects received paroxetine 20 mg or placebo once daily for 12 days and an HYD 20-mg tablet on day 10 of each period.FindingsHydrocodone mean Cmax and t½ and median Tmax values were similar with paroxetine or placebo coadministration (16.8 vs 15.9 ng/mL, 8.5 vs 8.4 hours, and 18.0 vs 18.0 hours, respectively), as were mean AUC0-t and AUC0-∞ values (342.9 vs 325.3 ng · h/mL and 346.3 vs 328.5 ng · h/mL). The 90% CIs of the geometric mean ratios of the hydrocodone AUC and Cmax values were fully within the predetermined range of 80% to 125%, suggesting that there was no effect of multiple doses of paroxetine on systemic exposure to hydrocodone. Mean hydromorphone AUC0-t and Cmax values were decreased with paroxetine versus placebo (0.64 vs 3.8 ng · h/mL and 0.06 vs 0.19 ng/mL), whereas Tmax values remained similar (18.0 vs 16.1 hours, respectively). The mean hydromorphone AUC0-∞ value could not be calculated. Both regimens were well tolerated; after HYD administration, the numbers of adverse events were similar between the 2 treatment regimens, and all adverse events were mild.ImplicationsIn this study, the coadministration of single-dose HYD with paroxetine at steady state did not alter systemic exposure to hydrocodone, suggesting that HYD can be coadministered with CYP2D6 inhibitors at therapeutic doses, without dosage modification.Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

30 keywords...

hide…