Effects of paroxetine, a CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone after coadministration with a single-entity, once-daily, extended-release hydrocodone tablet.
OBJECTIVE
A 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.


METHODS
In 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.


RESULTS
Hydrocodone 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.


CONCLUSIONS
In 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.
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut. Electronic address: Ram.Kapil@pharma.com.
Ram P
RP
Kapil
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut.
Kristen
K
Friedman
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut.
Alessandra
A
Cipriano
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut.
Gregory
G
Michels
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut.
Manjunath
M
Shet
PPD, Inc, Austin, Texas.
Sabiha A
SA
Mondal
Department of Medical Research, Purdue Pharma L.P., Stamford, Connecticut.
Stephen C
SC
Harris
D000328:Adult; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006853:Hydrocodone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004091:Hydromorphone / Q000378:metabolism; D008297:Male; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology*; D013607:Tablets
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003692:Delayed-Action Preparations; D013607:Tablets; D017374:Paroxetine; D006853:Hydrocodone; D003577:Cytochrome P-450 Enzyme System; D004091:Hydromorphone
CYP2D6 inhibitor; drug–drug interaction; hydrocodone; hydromorphone; opioid; paroxetine; pharmacokinetics