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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.

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Related in: MedlinePlus

Analyses of dose proportionality with OROS® hydromorphone: (A) Cmax/dose; (B) AUC0–48/dose. Dashed lines represent 95% CI.
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Figure 3: Analyses of dose proportionality with OROS® hydromorphone: (A) Cmax/dose; (B) AUC0–48/dose. Dashed lines represent 95% CI.

Mentions: Mean dose-normalized pharmacokinetic parameters for OROS® hydromorphone after administration of 8, 16, 32, and 64 mg doses are shown in Table 3. Cmax and AUC increased linearly and in a manner proportional to the dose of OROS® hydromorphone. The slopes of dose-normalized Cmax and AUC vs. dose did not differ significantly from zero (P > 0.05; Figure 3). Inter-subject variability in pharmacokinetic parameters was similar across the doses except for high variability of Cmax following the 8-mg dose. This was mainly due to one subject with a high concentration (>5 times the mean). When this subject was excluded, Cmax variability for the 8-mg dose was similar to the other doses. No significant gender-by-treatment interactions were observed (ANOVA model; data not shown).


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)

Analyses of dose proportionality with OROS® hydromorphone: (A) Cmax/dose; (B) AUC0–48/dose. Dashed lines represent 95% CI.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Analyses of dose proportionality with OROS® hydromorphone: (A) Cmax/dose; (B) AUC0–48/dose. Dashed lines represent 95% CI.
Mentions: Mean dose-normalized pharmacokinetic parameters for OROS® hydromorphone after administration of 8, 16, 32, and 64 mg doses are shown in Table 3. Cmax and AUC increased linearly and in a manner proportional to the dose of OROS® hydromorphone. The slopes of dose-normalized Cmax and AUC vs. dose did not differ significantly from zero (P > 0.05; Figure 3). Inter-subject variability in pharmacokinetic parameters was similar across the doses except for high variability of Cmax following the 8-mg dose. This was mainly due to one subject with a high concentration (>5 times the mean). When this subject was excluded, Cmax variability for the 8-mg dose was similar to the other doses. No significant gender-by-treatment interactions were observed (ANOVA model; data not shown).

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