In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa).
A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m(-2). In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201+/-607 h ng ml(-1)) than those who did not (5024+/-978 h ng ml(-1)) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.
Bouligand
J
J
UPRES EA3535, Pharmacology and New Treatments of Cancers, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif 94800, France.
Boland
I
I
Valteau-Couanet
D
D
Deroussent
A
A
Kalifa
C
C
Hartmann
O
O
Vassal
G
G
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000628:therapy; D010599:Pharmacokinetics; D013852:Thiotepa / Q000008:administration & dosage; D014182:Transplantation, Autologous
D018906:Antineoplastic Agents, Alkylating; D013852:Thiotepa; D002066:Busulfan; D008558:Melphalan