Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation

Summary:We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age o4 years) and 0.8 mg/kg (age X4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children o4 years as in children X4 years. Mean clearance was higher in children o4 years than in children X4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

Section: Bu Pharmacokineticssupporting

confidence: 74%

Section: Pharmacokinetics and Statistical Analysismentioning

confidence: 99%

Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity

Zwaveling¹,

Bredius

Cremers³

et al. 2004

“…BU. 4,8,10,[13][14][15][16][17][18] Nevertheless, the clinical outcomes and the study of pharmacokinetics (PK) of once-daily i.v. BU in Asian adult populations are still scanty.…”

Section: Introductionmentioning

confidence: 99%

Once-daily i.v. BU-based conditioning regimen before allogeneic hematopoietic SCT: a study of influence of GST gene polymorphisms on BU pharmacokinetics and clinical outcomes in Chinese patients

Yin

Yan

Zheng

et al. 2015

I.v. BU has been proven to have better bioavailability, reliable systemic drug exposure with more predictable blood levels and lower toxicity than oral BU when used as part of conditioning regimens before hematopoietic SCT (HSCT). Some studies have shown that once-daily i.v. BU had the same clinical efficacy as i.v. BU administered four times daily. To observe the clinical efficacy and pharmacokinetics (PK) of once-daily i.v. BU and to evaluate the influence of glutathione S-transferase (GST) gene polymorphisms on once-daily i.v. BU PK in adult Chinese patients with allogeneic HSCT, we analyzed 25 patients receiving related or unrelated donor transplant conditioned with i.v. BU-based regimens. With a median follow-up of 32.7 months, the 2-year OS and EFS were 64 and 63.8% for all the patients, respectively, and the 2-year cumulative incidence of relapse for all patients was 18.3%. On the basis of HPLC analysis, the mean clearance and mean daily area under the curve (AUC) of i.v. BU were calculated as 4.02 mL/min per kg and 3380.77 μM/min, respectively. The estimated C max was 1.031 ± 0.0325 μg/mL. The estimated t 1/2 and V d values were 3.618 ± 0.1932 h and 1.212 ± 0.0352 L/kg. The once-daily i.v. BU-based conditioning regimen was very well tolerated with minor toxicity in patients, most likely because of dose assurance with predictable PK. There was no GSTA1 *B/*B homozygous patient in our Chinese patients. A significant association between BU metabolism and GSTA1 polymorphism was observed. The GSTA1 *A/*B genotype group showed a significantly higher AUC (P o0.0001), higher C max (P = 0.0003) and lower clearance (P = 0.0007) than the GSTA1

“…3 A mean AUC of 1002 mM min per dose was reported for this dosing regimen. Schedules of 1.6 mg/kg every 12 h or 3.2 mg/kg every 24 h 4,5 were evaluated as alternatives to the every 6 h regimen. The efficacy and predictable blood concentrations from 3.2 mg/kg once daily dosing were further validated in other studies.…”

Section: Introductionmentioning

confidence: 99%

Reliability of a pretransplant i.v. BU test dose performed 2 weeks before myeloablative FluBu conditioning regimen

Beri

Chunduri

Sweiss

et al. 2009

A pretransplant test dose of i.v. BU was previously used in pediatric patients undergoing a reduced-intensity allogeneic hematopoietic SCT (HSCT). Here, we used a BU test dose in 23 adult patients who were not pancytopenic and underwent a myeloablative allogeneic HSCT prepared with fludarabine and i.v. BU (FluBU). Pharmacokinetics (PK) of BU were calculated after a test dose (0.8 mg/kg) was performed 2 weeks before transplant. Targeted BU area under the curve (AUC) range was 4800-5200 lM min. The mean BU dose calculated after the test dose was 3.5 ± 0.5 mg/kg. To validate the test dose, PK studies were repeated in 17 patients after the first dose of BU during the conditioning regimen. An AUC below the therapeutic value of 4000 lM min was observed in 23% of the patients receiving a wt-based dose and in 0% of patients whose dose was calculated on the basis of the test dose (P ¼ 0.03). In patients who had a test dose, a significant correlation (Po0.0001) between the first and subsequent doses of BU during the conditioning regimen was observed. Our findings may allow more centers to pursue transplant strategies with targeted BU by overcoming the time limitation for PK studies during the conditioning regimen.