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Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients
Author(s) -
Nath Christa E.,
Earl John W.,
Pati Nalini,
Stephen Katherine,
Shaw Peter J.
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03166.x
Subject(s) - pharmacokinetics , dosing , medicine , pharmacology , busulfan , transplantation , hematopoietic stem cell transplantation
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetics of oral busulphan given four times daily has been extensively studied. • Large inter‐ and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring. • However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6‐h dosing interval, due to late absorption in some patients. • Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose. WHAT THIS STUDY ADDS • Inter‐ and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable. • Children with immune deficiencies, in particular, have widely variable exposure. 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 .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.