Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects.
| Autor: | Suri A; Eli Lilly and Company, Indianapolis, IN, USA. Suri_Ajit@lilly.com, Reddy S, Gonzales C, Knadler MP, Branch RA, Skinner MH |
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| Jazyk: | angličtina |
| Zdroj: | International journal of clinical pharmacology and therapeutics [Int J Clin Pharmacol Ther] 2005 Feb; Vol. 43 (2), pp. 78-84. |
| DOI: | 10.5414/cpp43078 |
| Abstrakt: | Objective: To compare the pharmacokinetics of single-dose duloxetine in cirrhotic and healthy subjects. Methods: An open-label inpatient study compared duloxetine pharmacokinetics in six subjects with moderate liver cirrhosis (Child-Pugh class B) to those in six healthy subjects. Subjects received a single 20 mg capsule of duloxetine following overnight fasting. Blood samples were collected up to 120 h post dose for determination of plasma concentrations of duloxetine and its major metabolites using a validated LC/MS/MS method. Plasma concentration-time data for duloxetine and its major metabolites were analyzed by noncompartmental methods. Specific pharmacokinetic parameters were assessed statistically using a mixed-effects model. Results: Duloxetine apparent clearance was significantly lower (24 vs 160 l/h, p < 0.05) and AUC values were substantially higher (775 vs 268 ng x (h/ml) in cirrhotic compared to healthy subjects. The half-life of duloxetine was about three times longer (47.8 vs 13.5 h) in cirrhotic than in healthy subjects (p < 0.05). In contrast, there was no significant difference in Cmax or apparent volume of distribution between the two groups. The metabolites exhibited lower levels and longer half-lives in cirrhotic subjects compared to healthy subjects. The lower clearance and slower elimination of duloxetine in cirrhotic individuals is likely attributable to impaired duloxetine metabolism. Conclusions: The rate of duloxetine elimination is reduced for cirrhotic subjects, making dosage adjustments appropriate. Based on simulations, the duloxetine dose for at least an initial treatment period may need to be reduced and/or less frequently administered for patients with moderate cirrhosis. |
| Databáze: | MEDLINE |
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