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05-12-2017 | Leukemia | Article

Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

Journal: Cancer Chemotherapy and Pharmacology

Authors: Swantje Völler, Uwe Pichlmeier, Anke Zens, Georg Hempel

Publisher: Springer Berlin Heidelberg

Abstract

Purpose

The objective of this study was to assess the pharmacokinetics of recombinant asparaginase (rASNase, Spectrila^®) in children with acute lymphoblastic leukemia using a population pharmacokinetic approach in order to explore potential dosing recommendations.

Methods

Data on serum asparaginase activities of 124 children from three clinical studies were included in the analysis, covering an age range from 3 days to 17 years. Most patients received 5000 U/m² rASNase intravenously every 3 days. The non-linear mixed effects modelling software (NONMEM^®) was utilized to identify drivers of rASNase pharmacokinetics in children. Different dose adjustments were simulated for their ability to increase rASNase trough activities in children who do not reach the threshold of 100 U/L.

Results

A two-compartment model with allometric weight scaling (0.75 on clearance [CL] and inter-compartmental clearance [Q] and 1 on central [V ₁] and peripheral [V ₂] volume of distribution) was the best model to describe the pharmacokinetics of rASNase. PK parameters for the median child (19.5 kg) were: CL = 0.0592 L/h, V ₁ = 1.18 L, Q = 0.307 L/h, V ₂ = 0.316 L. Organ functions, such as liver or kidney function and laboratory values, such as fibrinogen or antithrombin III levels, showed no influence on rASNase pharmacokinetics. In simulations, changing the administration interval from 72 to 48 h was appropriate to maintain rASNase activities above the therapeutic threshold, in patients with activities below 100 U/L 72 h after the first dose.

Conclusions

Drug monitoring is recommended to identify patients with insufficient ASNase trough activities in serum and to modify the treatment schedule, if necessary. Shortening of the treatment interval might be preferable over increasing the rASNase dose.

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