Limits...
Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone.

Sathyan G, Xu E, Thipphawong J, Gupta SK - BMC Clin Pharmacol (2007)

Bottom Line: Median Tmax (12.0-16.0 hours) and mean t1/2 (10.6-11.0 hours) were found to be independent of dose.Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

View Article: PubMed Central - HTML - PubMed

Affiliation: ALZA Corporation, Mountain View, CA, USA. gsathyan@alzus.jnj.com

ABSTRACT

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).

Conclusion: The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

Show MeSH

Related in: MedlinePlus

Mean plasma hydromorphone concentrations over time after administration of single-dose OROS® hydromorphone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC1808051&req=5

Figure 1: Mean plasma hydromorphone concentrations over time after administration of single-dose OROS® hydromorphone.

Mentions: The plasma concentration-time profiles of the four OROS® hydromorphone doses tested are shown in Figure 1. Following a single oral dose of OROS® hydromorphone, plasma mean concentrations gradually increase over 6 to 8 hours, and thereafter are sustained at or near maximum levels up to approximately 30 hours post-dose. The means of untransformed pharmacokinetic parameters and the medians of Tmax are shown in Table 2. Maximum plasma hydromorphone concentrations were achieved approximately 12 to 16 hours after administration, with no significant dose effect observed. Mean values for t1/2 were similar for the various doses (10.6–11.0 hours). Analysis of Cmax, AUC0-t, and AUC0–∞ by dose indicated that the relationship was linear (P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05; Figure 2).


Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone.

Sathyan G, Xu E, Thipphawong J, Gupta SK - BMC Clin Pharmacol (2007)

Mean plasma hydromorphone concentrations over time after administration of single-dose OROS® hydromorphone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808051&req=5

Figure 1: Mean plasma hydromorphone concentrations over time after administration of single-dose OROS® hydromorphone.
Mentions: The plasma concentration-time profiles of the four OROS® hydromorphone doses tested are shown in Figure 1. Following a single oral dose of OROS® hydromorphone, plasma mean concentrations gradually increase over 6 to 8 hours, and thereafter are sustained at or near maximum levels up to approximately 30 hours post-dose. The means of untransformed pharmacokinetic parameters and the medians of Tmax are shown in Table 2. Maximum plasma hydromorphone concentrations were achieved approximately 12 to 16 hours after administration, with no significant dose effect observed. Mean values for t1/2 were similar for the various doses (10.6–11.0 hours). Analysis of Cmax, AUC0-t, and AUC0–∞ by dose indicated that the relationship was linear (P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05; Figure 2).

Bottom Line: Median Tmax (12.0-16.0 hours) and mean t1/2 (10.6-11.0 hours) were found to be independent of dose.Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05).The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

View Article: PubMed Central - HTML - PubMed

Affiliation: ALZA Corporation, Mountain View, CA, USA. gsathyan@alzus.jnj.com

ABSTRACT

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).

Conclusion: The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.

Show MeSH
Related in: MedlinePlus