Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients.
OBJECTIVE
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.
Nath
Christa E
CE
Departments of Biochemistry, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. christan@chw.edu.au
Earl
John W
JW
Pati
Nalini
N
Stephen
Katherine
K
Shaw
Peter J
PJ
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D008297:Male; D015588:Observer Variation; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D002066:Busulfan