Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone.
BACKGROUND
The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS Push-Pull osmotic pump technology.


METHODS
In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0-infinity). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0-infinity, and Cmax was used to establish dose linearity and proportionality.


RESULTS
The study was completed by 31 of 32 subjects. Median Tmax (12.0-16.0 hours) and mean t1/2 (10.6-11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0-48, and AUC0-infinity by dose indicated that the relationship was linear (slope, P < or = 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).


CONCLUSIONS
The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.
Sathyan
Gayatri
G
ALZA Corporation, Mountain View, CA, USA. gsathyan@alzus.jnj.com
Xu
Emily
E
Thipphawong
John
J
Gupta
Suneel K
SK
D000328:Adult; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D004091:Hydromorphone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009294:Narcotics / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D009294:Narcotics; D004091:Hydromorphone