Population pharmacokinetics and pharmacokinetics/pharmacodynamics of bendamustine in pediatric patients with relapsed/refractory acute leukemia

Abstract

Objective:

The pharmacokinetic (PK) profile of bendamustine has been characterized in adults with indolent non-Hodgkin lymphoma (NHL), but remains to be elucidated in pediatric patients with hematologic malignancies. This analysis used data from a nonrandomized pediatric study in patients with relapsed/refractory acute lymphocytic leukemia or acute myeloid leukemia.

Methods:

Bendamustine 90 or 120 mg/m² (60-minute infusion) was administered on days 1 and 2 of 21 day cycles. The population PK base model was adjusted for body surface area (BSA), and the appropriateness of the final model was evaluated by visual predictive check. A covariate analysis explored PK variability. Bayesian PK parameter estimates and concentration–time profiles for each patient were generated. Bendamustine PK in pediatric patients was compared with that of adults with indolent NHL. PK/pharmacodynamic analyses were conducted for fatigue, nausea, vomiting, and infection.

Results:

Thirty-eight patients (median age: 7 years; range: 1–19 years) receiving bendamustine 120 mg/m² and an additional five patients receiving bendamustine 90 mg/m² (median age: 12 years; range: 8–14 years) were included in the population PK analysis. Peak plasma concentrations of bendamustine (C_max) occurred at the end of infusion (about 1 h). Decline from peak showed a rapid distribution phase (t_½α = 0.308 h) and a slower elimination phase (t_½β = 1.47 h). Model-predicted mean C_max and area under the curve values from time 0–24 h were 6806 ng/mL and 8240 ng*h/mL, respectively. When dosed based upon BSA, it appeared that age, body weight, race, mild renal (n = 3) or hepatic (n = 2) dysfunction, cancer type, and cytochrome P450 1A2 inhibitors (n = 17) or inducers (n = 3) did not affect systemic exposure, which was comparable between pediatric and adult patients. Infection was the only adverse event associated with bendamustine C_max. However, due to the small sample size for some subgroups, the observed trends should be interpreted with caution.

Conclusions:

At the recommended dose (120 mg/m²), bendamustine systemic exposure was similar across the pediatric population and comparable to adults. The similarity in exposure despite the large range of BSA across pediatric and adult populations confirms the appropriateness of BSA-based dosing, which was utilized to attain systemic exposures in pediatric patients reflective of the therapeutic range in adults. Probability of occurrence of infection increased with higher bendamustine C_max.

Keywords::

• Bendamustine
• Body surface area
• Exposure
• Pediatric
• Pharmacokinetics

Transparency

Declaration of funding

This research was sponsored by and conducted by Teva Branded Pharmaceutical Products R&D Inc., Frazer, PA, USA, and conducted in collaboration with Cognigen Corporation, Buffalo, NY, USA. Funding for editorial support was provided by Teva Branded Pharmaceutical Products R&D Inc., to The Curry Rockefeller Group LLC, Tarrytown, NY, USA.

Declaration of financial/other relationships

M.D. has disclosed that, during part of the development of the manuscript, she was an employee of Teva. M.B., E.H., and P.R. have disclosed that they are employees and shareholders of Teva. G.M. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article. T.G. and L.P. have disclosed that they are employees of Cognigen, which received research funding to develop the model and conduct the analysis for this study.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Julie Passarell MA of Cognigen Corporation, Buffalo, NY, USA, who performed the PD analyses, and Mihaela Munteanu MS of Teva Branded Pharmaceuticals Products R&D Inc., Frazer, PA, USA, for her review of this manuscript. Writing and editorial assistance were provided by Kathleen Wildasin MA and Jennifer Kuo PharmD of The Curry Rockefeller Group, which was funded by Teva.

Previous presentations: Partial results of the study were presented as abstracts: Darwish M, Megason G, Bond M, et al. Pharmacokinetics (PK) of bendamustine in pediatric patients with relapsed/refractory acute leukemia. J Clin Oncol 2012;30(Suppl):abstract 9547; Darwish M, Megason G, Bond M, et al. Bendamustine pharmacokinetics (PK) in pediatric patients with relapsed/refractory acute leukemia. Haematologica 2012;97(s1):488, Abstract 1175