title: Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.
abstract: BACKGROUND
  Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored.
  
  
  METHODS
  A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure.
  
  
  RESULTS
  No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC's reported in HIV-negative recipients, when similar trough levels were targeted.
  
  
  CONCLUSIONS
  In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.
authors.affiliation: Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. E.M.vanmaarseveen@UMCUtrecht.nl
authors.forename: Erik M
authors.initials: EM
authors.lastname: van Maarseveen
authors.forename: Heleen A
authors.initials: HA
authors.lastname: Crommelin
authors.forename: Tania
authors.initials: T
authors.lastname: Mudrikova
authors.forename: Marcel P H
authors.initials: MP
authors.lastname: van den Broek
authors.forename: Arjan D
authors.initials: AD
authors.lastname: van Zuilen
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000097:blood / Q000601:surgery* / Q000821:virology; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D016903:Drug Monitoring; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015658:HIV Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000601:surgery* / Q000821:virology; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010865:Pilot Projects; D019438:Ritonavir / Q000627:therapeutic use*; D016559:Tacrolimus / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007166:Immunosuppressive Agents; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D016559:Tacrolimus