title: Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts.
abstract: OBJECTIVE
  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) (r² = 0.77, P < 0.0001) at each analysis time point. Logistic regression showed a relationship between C(min,TN) in the 380 patients and pneumonia occurrence, but not between C(min,TN) and stomatitis, rejection, or death.
  
  
  CONCLUSIONS
  In this study, the pharmacokinetic profile of sirolimus in hepatic allograft patients was consistent with that of renal transplantation recipients. With the exception of pneumonia, no correlation was observed between C(min,TN) and the occurrence of adverse events of interest.
authors.affiliation: University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital, Berne, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Reichen
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Indranil
authors.initials: I
authors.lastname: Bhattacharya
authors.forename: Kyle
authors.initials: K
authors.lastname: Matschke
authors.forename: Eric
authors.initials: E
authors.lastname: Maller
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
mesh_terms: D000328:Adult; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D048550:Hepatic Insufficiency / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015994:Incidence; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D016031:Liver Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011014:Pneumonia / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control; D012306:Risk; D012720:Severity of Illness Index; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013280:Stomatitis / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus