Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts

Purpose To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C min,TN ) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients. Methods Dense s...

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Veröffentlicht in:European journal of clinical pharmacology 2012-05, Vol.68 (5), p.589-597
Hauptverfasser: Reichen, Jürg, Stickel, Felix, Bhattacharya, Indranil, Matschke, Kyle, Maller, Eric, Korth-Bradley, Joan
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Sprache:eng
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Zusammenfassung:Purpose To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C min,TN ) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients. Methods Dense sampling of sirolimus was performed over a single daily-dosing interval in 11 hepatic allograft recipients on day 28 and at 3 months after start of treatment. Serial trough concentration sampling was performed in 380 hepatic allograft recipients on days 1, 7, 14, 28, 42, 60, 90, 180, 270 and 360 after start of treatment. Occurrence of stomatitis, pneumonia, rejection, and death were collected for 360 days after start of treatment. Noncompartmental pharmacokinetic parameters were analyzed in the 11 densely sampled patients; C min,TN was determined in the 380 patients. Results Mean maximum concentration (C max ), time to C max (t max ), area under the curve for the given dose interval (AUC tau ), and whole blood oral clearance at 3 months were 20.8 ± 7.6 ng/mL, 3 ± 1 h, 338 ± 144 ng·h/mL, and 10.0 ± 5.6 L/hr, respectively. In the 11 densely sampled patients, linear regression showed that C min,TN was highly predictive of AUC tau (r 2  = 0.77, P  
ISSN:0031-6970
1432-1041
DOI:10.1007/s00228-011-1172-7