Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients

Abstract

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.

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…18,29,30 Despite these improvements, inter-patient variability still exists and the percentage of patients reaching the target AUC after the first dose remains low. 8,18,26,31,32 Several factors have been identified to account for differences such as sex, weight, age or BSA. 4,26,33 In this paper, we examined whether the polymorphisms in the GSTA1, GSTM1 and GTP1 genes also contributed to this variability.…”

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

“…9,11 BU metabolism is affected by GST enzyme activity, which is influenced by age, disease condition and co-medication. 2,[12][13][14] Body weight and body surface area have been also shown to contribute to PK variability. [15][16][17][18][19] Nevertheless, a large proportion of BU variability remains unexplained 20 and could be due to GST polymorphisms influencing GST activity [21][22][23][24][25] (Table 1).…”

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

“…BU in children. Tran et al 12 obtained a BU clearance of 4.49 ml/min per kg for patients younger than 6 years of age and 3.35 ml/min per kg for those older than 6 years; Schechter et al 41 estimated that BU clearance is 3.8 ml/min per kg in children younger than 4 years versus 3.0 ml/min per kg in those older than 4 years; Nath et al 42 demonstrated a linear decrease in BU clearance from 4.8 ml/min per kg in infancy to 3.3 ml/min per kg at 10 years and to 2.0 ml/min per kg at 20 years; and Vassal et al 35 reported a clearance of 3.7 ml/min per kg in early infancy, 4 ml/min per kg at 1 year of age and a linear decline to about 2.3 ml/min per kg in adulthood. We found that the younger patients have not only a higher BU clearance but also a less predictable PK profile.…”