Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring.
We prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 microMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.
International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy. j.gaziev@fondazioneime.org
Javid
J
Gaziev
Laurent
L
Nguyen
Christian
C
Puozzo
Alessia Francesca
AF
Mozzi
Marialuisa
M
Casella
Michela
M
Perrone Donnorso
Paolo
P
Gravina
Pietro
P
Sodani
Marco
M
Marziali
Antonella
A
Isgrò
Maria Domenica
MD
Simone
Marco
M
Andreani
Amanda
A
Formosa
Manuela
M
Testi
Giorgio
G
Federici
Sergio
S
Bernardini
Guido
G
Lucarelli
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D018572:Disease-Free Survival; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D011446:Prospective Studies; D013789:Thalassemia / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D016896:Treatment Outcome; D055815:Young Adult
D017931:DNA Primers; D007166:Immunosuppressive Agents; D005982:Glutathione Transferase; D002066:Busulfan