title: Association between cyclosporine concentrations at 2 hours post-dose and clinical outcomes in de novo lung transplant recipients.
abstract: BACKGROUND
  The objective of this study was to investigate the relationship between cyclosporine (CsA) pharmacokinetic parameters and clinical outcomes after lung transplantation.
  
  
  METHODS
  Data from 48 lung or heart/lung transplant recipients originally recruited to a randomized, prospective clinical trial of Sandimmune vs Neoral and followed for 12 months were included in this study. CsA dosing was based on the trough concentration. CsA concentrations at 0 (C0), 2 (C2), and 6 (C6) hours post-dosing were obtained at 1, 2, 3, 4, 13, 26, 39, and 52 post-operative weeks. Based on their average C2 levels in the first post-transplant month, patients were stratified retrospectively into Low C2 (<1,000 microg/liter, n = 18), Intermediate C2 (1,000-1,500 microg/liter, n = 16) and High C2 (>1,500 microg/liter, n = 14) Groups.
  
  
  RESULTS
  Cyclosporine C2 was the best single-point determinant (r2 = 0.934) for area-under-the-concentration-time curve (AUC(0-6 hours)) compared with C0 (r2 = 0.267) or C6 (r2 = 0.304). The mean +/- SD values of CsA C2 and AUC(0 to 6 hours) in the first year post-transplant were significantly lower in patients with >2 rejection episodes compared with those with < or =2 rejection episodes (C2: 875 +/- 546 microg/liter vs 1,114 +/- 633 microg/liter, p = 0.01; AUC(0-6 hours): 4,036 +/- 1,904 microg x hour/liter vs 4,870 +/- 2,182 microg x hour/liter; p = 0.01) whereas C0 and C6 did not differ. Patients in the Intermediate C2 Group were free from rejection episodes for a significantly longer duration (p < 0.001) and had significantly higher predicted forced expiratory volume in 1 second (%) values (p < 0.001) compared with the Low and High C2 Groups. The percentage of increase in serum creatinine concentration by the end of first month post-transplant was significantly higher in the Intermediate C2 Group (p < 0.003).
  
  
  CONCLUSIONS
  CsA C2 concentrations correlated better with the incidence of multiple rejections after lung transplantation than did C0 or C6. C2 concentrations between 1,000 and 1,500 microg/liter within the first post-operative month may be associated with better graft outcomes and improved pulmonary function and worsened renal function.
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA. fatemeh@uri.edu
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
authors.forename: Liliana
authors.initials: L
authors.lastname: Gonzalez
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Trull
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007668:Kidney / Q000502:physiology; D008168:Lung / Q000502:physiology; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012129:Respiratory Function Tests; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine