title: Busulfan dosing algorithm and sampling strategy in stem cell transplantation patients.
abstract: OBJECTIVE
  The aim of this investigation was to develop a model-based dosing algorithm for busulfan and identify an optimal sampling scheme for use in routine clinical practice.
  
  
  METHODS
  Clinical data from an ongoing study (n = 29) in stem cell transplantation patients were used for the purposes our analysis. A one compartment model was selected as basis for sampling optimization and subsequent evaluation of a suitable dosing algorithm. Internal and external model validation procedures were performed prior to the optimization steps using ED-optimality criteria. Using systemic exposure as parameter of interest, dosing algorithms were considered for individual patients with the scope of minimizing the deviation from target range as determined by AUC(0,6 h).
  
  
  RESULTS
  Busulfan exposure after oral administration was best predicted after the inclusion of adjusted ideal body weight and alanine transferase as covariates on clearance. Population parameter estimates were 3.98 h(-1), 48.8 l and 12.3 l h(-1) for the absorption rate constant, volume of distribution and oral clearance, respectively. Inter-occasion variability was used to describe the differences between test dose and treatment. Based on simulation scenarios, a dosing algorithm was identified, which ensures target exposure values are attained after a test dose. Moreover, our findings show that a sparse sampling scheme with five samples per patient is sufficient to characterize the pharmacokinetics of busulfan in individual patients.
  
  
  CONCLUSIONS
  The use of the proposed dosing algorithm in conjunction with a sparse sampling scheme may contribute to considerable improvement in the safety and efficacy profile of patients undergoing treatment for stem cell transplantation.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Francine A
authors.initials: FA
authors.lastname: de Castro
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: Chiara
authors.initials: C
authors.lastname: Piana
authors.affiliation: Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Belinda P
authors.initials: BP
authors.lastname: Simões
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Lanchote
authors.affiliation: Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.|Clinical Pharmacology & Therapeutics, University College London, London, UK.
authors.forename: O
authors.initials: O
authors.lastname: Della Pasqua
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D054796:Drug Dosage Calculations; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan
keywords: busulfan; dosing algorithm; population pharmacokinetics; sparse sampling; stem cell transplantation; therapeutic drug monitoring
references.citation: Biol Blood Marrow Transplant. 2002;8(9):493-500
references.pmid: 12374454
references.citation: Cancer Sci. 2012 Sep;103(9):1688-94
references.pmid: 22631696
references.citation: Biol Blood Marrow Transplant. 2008 Feb;14(2):220-8
references.pmid: 18215782
references.citation: Biol Blood Marrow Transplant. 2002;8(3):145-54
references.pmid: 11939604
references.citation: Clin Cancer Res. 2011 Nov 1;17(21):6867-77
references.pmid: 21918171
references.citation: Pediatr Transplant. 2011 Sep;15(6):580-8
references.pmid: 21736681
references.citation: Bone Marrow Transplant. 2011 Nov;46(11):1418-25
references.pmid: 21132026
references.citation: Comput Methods Programs Biomed. 2005 Sep;79(3):241-57
references.pmid: 16023764
references.citation: Bone Marrow Transplant. 2007 Apr;39(7):397-400
references.pmid: 17322933
references.citation: Blood. 1992 May 1;79(9):2475-9
references.pmid: 1571560
references.citation: Blood. 1997 Apr 15;89(8):3055-60
references.pmid: 9108427
references.citation: Eur J Clin Pharmacol. 2011 May;67 Suppl 1:5-16
references.pmid: 20340012
references.citation: Jpn J Clin Oncol. 2005 Jul;35(7):400-3
references.pmid: 15976066
references.citation: Rapid Commun Mass Spectrom. 2012 Jun 30;26(12):1437-46
references.pmid: 22592987
references.citation: Ther Drug Monit. 2008 Feb;30(1):75-83
references.pmid: 18223466
references.citation: Pediatr Blood Cancer. 2010 Feb;54(2):291-8
references.pmid: 19743300
references.citation: Ther Drug Monit. 2006 Feb;28(1):62-6
references.pmid: 16418695
references.citation: Pediatr Transplant. 2009 Dec;13(8):971-6
references.pmid: 19032412
references.citation: Blood. 2010 Jun 3;115(22):4597-604
references.pmid: 20237319
references.citation: Eur J Cancer. 2012 Nov;48(16):3063-72
references.pmid: 22742881
references.citation: Bone Marrow Transplant. 1994 Nov;14(5):759-65
references.pmid: 7889009
references.citation: J Clin Pharmacol. 2013 Nov;53(11):1205-11
references.pmid: 23955479
references.citation: Cancer Chemother Pharmacol. 2003 Sep;52(3):209-16
references.pmid: 12811512
references.citation: Anticancer Res. 2010 Jul;30(7):2977-84
references.pmid: 20683042
references.citation: Korean J Physiol Pharmacol. 2012 Aug;16(4):273-80
references.pmid: 22915993
references.citation: Bone Marrow Transplant. 2001 Oct;28(8):743-51
references.pmid: 11781625
references.citation: J Clin Pharmacol. 2010 Nov;50(11):1292-300
references.pmid: 20075185
references.citation: Clin Pharmacol Ther. 2007 Jul;82(1):17-20
references.pmid: 17571070
references.citation: Biol Blood Marrow Transplant. 2012 Feb;18(2):295-301
references.pmid: 21801704
references.citation: Rapid Commun Mass Spectrom. 2005;19(12):1666-74
references.pmid: 15912469
references.citation: Anticancer Drugs. 2004 Jun;15(5):453-9
references.pmid: 15166618
references.citation: Bone Marrow Transplant. 2001 Oct;28(7):657-64
references.pmid: 11704788
references.citation: Clin Pharmacokinet. 2007;46(3):221-34
references.pmid: 17328581
references.citation: Bone Marrow Transplant. 2010 Feb;45(2):249-53
references.pmid: 19543331
references.citation: Bone Marrow Transplant. 2004 Jun;33(12):1191-9
references.pmid: 15122310
references.citation: J Clin Pharmacol. 1997 Jun;37(6):486-95
references.pmid: 9208355
references.citation: Br J Clin Pharmacol. 2008 Jul;66(1):50-9
references.pmid: 18341668
references.citation: Expert Opin Drug Metab Toxicol. 2013 Mar;9(3):333-47
references.pmid: 23157726
references.citation: Biol Blood Marrow Transplant. 2013 Jul;19(7):1033-9
references.pmid: 23583825
references.citation: Anticancer Res. 1994 Nov-Dec;14(6A):2363-70
references.pmid: 7825973
references.citation: Bone Marrow Transplant. 1997 Sep;20(5):347-54
references.pmid: 9339748
references.citation: Expert Opin Drug Metab Toxicol. 2009 Aug;5(8):957-69
references.pmid: 19611402
references.citation: Clin Pharmacokinet. 2012 May 1;51(5):331-45
references.pmid: 22455797
references.citation: Comput Methods Programs Biomed. 1999 Apr;59(1):19-29
references.pmid: 10215174
references.citation: Daru. 2011;19(3):216-23
references.pmid: 22615660
references.citation: Cancer Chemother Pharmacol. 2014 Nov;74(5):927-38
references.pmid: 25163570
references.citation: J Clin Pharmacol. 2013 Mar;53(3):264-75
references.pmid: 23444282