title: Software for dosage individualization of voriconazole for immunocompromised patients.
abstract: The efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.
authors: School of Translational Medicine, The University of Manchester, Manchester Academic Health Science Centre, National Institute for Health Research Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester National Health Service, Foundation Trust, Manchester, United Kingdom. william.hope@liverpool.ac.uk
authors: William W
authors: WW
authors: Hope
authors: Michael
authors: M
authors: Vanguilder
authors: J Peter
authors: JP
authors: Donnelly
authors: Nicole M A
authors: NM
authors: Blijlevens
authors: Roger J M
authors: RJ
authors: Brüggemann
authors: Roger W
authors: RW
authors: Jelliffe
authors: Michael N
authors: MN
authors: Neely
mesh_terms: D000328:Adult; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host / Q000187:drug effects*; D008962:Models, Theoretical; D011743:Pyrimidines / Q000627:therapeutic use*; D012984:Software; D014230:Triazoles / Q000627:therapeutic use*; D065819:Voriconazole
chemical_list: D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole
references: Antimicrob Agents Chemother. 2012 Jan;56(1):526-31
references: 22064545
references: J Antimicrob Chemother. 2010 Jan;65(1):107-13
references: 19933691
references: N Engl J Med. 2002 Aug 8;347(6):408-15
references: 12167683
references: Clin Infect Dis. 2012 Aug;55(3):381-90
references: 22610925
references: Ther Drug Monit. 2008 Feb;30(1):67-74
references: 18223465
references: Trends Microbiol. 2010 May;18(5):195-204
references: 20207544
references: Ann Pharmacother. 2011 Jun;45(6):757-63
references: 21652786
references: Proc Annu Symp Comput Appl Med Care. 1994;:972
references: 7950076
references: Clin Infect Dis. 2002 Mar 1;34(5):563-71
references: 11807679
references: Clin Pharmacokinet. 2011 Mar;50(3):143-89
references: 21294595
references: Antimicrob Agents Chemother. 2012 Sep;56(9):4793-9
references: 22751544
references: J Infect Dis. 2012 Aug 1;206(3):442-52
references: 22634880
references: Antimicrob Agents Chemother. 2006 Apr;50(4):1570-2
references: 16569888
references: Antimicrob Agents Chemother. 2011 Oct;55(10):4782-8
references: 21768513
references: Antimicrob Agents Chemother. 2010 Oct;54(10):4446-50
references: 20625156
references: Clin Infect Dis. 2012 Oct;55(8):1080-7
references: 22761409
references: Clin Infect Dis. 2010 Jan 1;50(1):27-36
references: 19951112
references: Clin Infect Dis. 2008 Jan 15;46(2):201-11
references: 18171251
references: J Clin Pharmacol. 2006 Feb;46(2):235-43
references: 16432276
references: Lancet. 2005 Oct 22-28;366(9495):1435-42
references: 16243088