title: A phase II trial of liposomal busulphan as an intravenous myeloablative agent prior to stem cell transplantation: 500 mg/m(2) as a optimal total dose for conditioning.
abstract: We conducted a phase I/II trial, to evaluate the efficacy and safety of an intravenous liposomal formulation of busulphan (LBu) as a myeloablative agent for stem cell transplantation (SCT). The liposomal busulphan was administered as a 3 h infusion twice daily over 4 consecutive days. Six adults received 1.6-2 mg/kg/dose and 18 children received 1.8-3 mg/kg/dose. Pharmacokinetic parameters were studied after the first and the last dose of busulphan. No significant difference in clearance, AUC, elimination half-lives or distribution volume between the first and the last dose was found in either groups. A significantly (P < 0.005) higher clearance was observed in children after the first and the last dose (3.61 and 3.79 ml/min/kg, respectively) compared to adults (2.40 and 2.33 ml/min/kg, respectively). The elimination half-lives after the first and the last dose were significantly (P < 0.005) shorter in children (2.59 and 2.72 h, respectively) compared to adults (3.35 and 3.61 h, respectively). Clearance correlated significantly with age. However, no significant correlation with age was observed when clearance was adjusted to the body surface area. Two cases of VOD following a total dose of 24 mg/kg were observed. Six patients experienced mucositis. No other organ toxicity was observed. We conclude that intravenous liposomal busulphan pharmacokinetics is age dependent. A dosage schedule based on body surface area should be used especially in young children to reduce the age-dependent difference in kinetics. An intravenous liposomal dose of busulphan of 500 mg/m(2) is suggested to reach a similar systemic exposure and myeloablative effect in both children and adults. Moreover, the novel liposomal form of busulphan showed a favorable toxicity profile and seems safe as a part of the high-dose therapy prior to SCT.
authors.affiliation: Laboratory of Hematology, Division of Hematology, Department of Medicine, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Hassan
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.forename: Z
authors.initials: Z
authors.lastname: Hassan
authors.forename: T
authors.initials: T
authors.lastname: Gungor
authors.forename: J
authors.initials: J
authors.lastname: Aschan
authors.forename: J
authors.initials: J
authors.lastname: Winiarski
authors.forename: P
authors.initials: P
authors.lastname: Hentschke
authors.forename: O
authors.initials: O
authors.lastname: Ringdén
authors.forename: S
authors.initials: S
authors.lastname: Eber
authors.forename: R
authors.initials: R
authors.lastname: Seger
authors.forename: P
authors.initials: P
authors.lastname: Ljungman
mesh_terms: D000328:Adult; D000367:Age Factors; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004337:Drug Carriers; D005260:Female; D030342:Genetic Diseases, Inborn / Q000628:therapy; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D006207:Half-Life; D019337:Hematologic Neoplasms / Q000628:therapy; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation / Q000009:adverse effects; D013280:Stomatitis / Q000139:chemically induced; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*
chemical_list: D004337:Drug Carriers; D007166:Immunosuppressive Agents; D008081:Liposomes; D003520:Cyclophosphamide; D002066:Busulfan; D008558:Melphalan