AIM: To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. METHODS: Busulphan (120 mg m(-2), 130 mg m(-2) or 3.2 mg kg(-1)) was administered over median 2.1 h. Blood samples (4-10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration-time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m(-2) dose in 13 children who had busulphan pharmacokinetic monitoring. RESULTS: Clearance of i.v. busulphan in 40 children was 4.78 +/- 2.93 l h(-1) (% CV 61%), 0.23 +/- 0.08 l h(-1) kg(-1) (% CV 35%) and 5.79 +/- 1.59 l h(-1) m(-2) (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h(-1)) and CL (l h(-1) kg(-1)), but not with CL (l h(-1) m(-2)). AUC normalized to the 130 mg m(-2) dose ranged from 14.1 to 56.3 mg l(-1) x h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h(-1) m(-2)) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. CONCLUSIONS: There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h(-1) m(-2)) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.
AIM: To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease. METHODS:Busulphan (120 mg m(-2), 130 mg m(-2) or 3.2 mg kg(-1)) was administered over median 2.1 h. Blood samples (4-10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration-time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m(-2) dose in 13 children who had busulphan pharmacokinetic monitoring. RESULTS: Clearance of i.v. busulphan in 40 children was 4.78 +/- 2.93 l h(-1) (% CV 61%), 0.23 +/- 0.08 l h(-1) kg(-1) (% CV 35%) and 5.79 +/- 1.59 l h(-1) m(-2) (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h(-1)) and CL (l h(-1) kg(-1)), but not with CL (l h(-1) m(-2)). AUC normalized to the 130 mg m(-2) dose ranged from 14.1 to 56.3 mg l(-1) x h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h(-1) m(-2)) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children. CONCLUSIONS: There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h(-1) m(-2)) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.
Authors: M Chandy; P Balasubramanian; S V Ramachandran; V Mathews; B George; D Dennison; R Krishnamoorthy; A Srivastava Journal: Bone Marrow Transplant Date: 2005-11 Impact factor: 5.483
Authors: Milly E de Jonge; Alwin D R Huitema; Selma M van Dam; Sjoerd Rodenhuis; Jos H Beijnen Journal: Anticancer Drugs Date: 2005-03 Impact factor: 2.248
Authors: Priska Kaufmann; Manuel Haschke; Michael Török; Johannes Beltinger; Katrijn Bogman; Markus Wenk; Luigi Terracciano; Stephan Krähenbühl Journal: Ther Drug Monit Date: 2006-12 Impact factor: 3.681
Authors: K Mamlouk; G Saracino; R B Berryman; J W Fay; L A Pineiro; E A Vance; M White; I Sandler; E D Agura Journal: Bone Marrow Transplant Date: 2005-04 Impact factor: 5.483
Authors: V Bertholle-Bonnet; N Bleyzac; C Galambrun; V Mialou; Y Bertrand; G Souillet; G Aulagner Journal: Ther Drug Monit Date: 2007-04 Impact factor: 3.681
Authors: Francine A de Castro; Chiara Piana; Belinda P Simões; Vera L Lanchote; O Della Pasqua Journal: Br J Clin Pharmacol Date: 2015-07-22 Impact factor: 4.335
Authors: Kristina M Brooks; Paul Jarosinski; Thomas Hughes; Elizabeth Kang; Nirali N Shah; John B Le Gall; Dennis D Hickstein; Suk See De Ravin; Jomy M George; Parag Kumar Journal: J Clin Pharmacol Date: 2017-12-14 Impact factor: 3.126
Authors: Imke H Bartelink; Jaap J Boelens; Robbert G M Bredius; Antoine C G Egberts; Chenguang Wang; Marc B Bierings; Peter J Shaw; Christa E Nath; George Hempel; Juliette Zwaveling; Meindert Danhof; Catherijne A J Knibbe Journal: Clin Pharmacokinet Date: 2012-05-01 Impact factor: 6.447
Authors: A Laura Nijstad; Shelby Barnett; Arief Lalmohamed; Inez M Bérénos; Elizabeth Parke; Vickyanne Carruthers; Deborah A Tweddle; Jordon Kong; C Michel Zwaan; Alwin D R Huitema; Gareth J Veal Journal: Eur J Cancer Date: 2021-12-02 Impact factor: 9.162