Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/refractory acute leukemia.

9547 Background: The PK profile of bendamustine in adult patients is well characterized. The objective of this analysis was to describe the pediatric PK profile of bendamustine relative to the adult PK profile and correlate the systemic exposure of bendamustine to efficacy and safety parameters. Methods: Samples were obtained after a single dose from patients aged 1-19 years with relapsed/refractory acute leukemia who were enrolled in an open-label, nonrandomized study of bendamustine (90–120 mg/m2, infused over 60 minutes). Samples were obtained prior to bendamustine infusion and preselected time points through 24 hours after start of infusion on day 1. Population PK modeling was performed using plasma concentration data from these patients. PK data from adults were used for comparison. Results: Systemic exposure of pediatric patients to bendamustine was similar to that obtained previously in adult patients. Mean Cmax was 6806 ng/mL and mean AUC0-24 was 8240 ng*hr/mL in pediatric patients, compared with a mean Cmax of 5746 ng/mL and AUC0-24 of 7121 ng*hr/mL in adults. Similarity in exposure despite the large range of body surface area across the pediatric and adult populations confirms appropriateness of the body surface area–based dosing scheme. In pediatric patients, age, race, sex, or disease state had no statistically significant effect on systemic exposure to bendamustine. No changes in systemic exposure to bendamustine in the presence of a CYP1A2 inhibitor/inducer were observed. Differences in PK were not observed in pediatric patients with mild renal impairment as compared with patients with normal renal function. Exposure in 2 pediatric patients with moderate hepatic dysfunction appeared to be higher. No clear exposure-response relationship was observed. Infection was the only adverse event for which the probability of occurrence increased with increase in exposure to bendamustine. Conclusions: The PK profile of bendamustine in pediatric patients was similar to the known PK profile in adults, demonstrating that exposures reflective of the therapeutic range in adults were attained following administration of 120 mg/m2 to pediatric patients. Support: Teva Pharmaceutical Industries Ltd., Frazer, PA.