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Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia

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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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Acknowledgements

We would like to thank the participating patients and their families for their contributions to this study.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Münster, Germany

    Swantje Völler & Georg Hempel

  2. Medac, Gesellschaft für klinische Spezialpräparate mbH, Wedel, Germany

    Uwe Pichlmeier & Anke Zens

  3. Leiden Academic Centre for Drug Research, Systems Biomedicine and Pharmacology, Leiden University, Leiden, The Netherlands

    Swantje Völler

Authors
  1. Swantje Völler
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  2. Uwe Pichlmeier
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  3. Anke Zens
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  4. Georg Hempel
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Corresponding author

Correspondence to Georg Hempel.

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Funding

This study was funded by medac GmbH (Wedel, Germany).

Conflict of interest

S. Völler and G. Hempel received funding from medac GmbH. U. Pichlmeier and A. Zens are employees of medac GmbH.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Electronic supplementary material

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Supplementary material 1 (DOCX 15 KB)

280_2017_3492_MOESM2_ESM.pdf

Plots of etas on clearance vs. demographic variables after incorporation of weight in the model (a: age, c: height, e: weight, g: body surface area) and plots of etas on central volume of distribution vs. demographic covariates after incorporation of weight into the model (b: age, d: height, f: weight, h: body surface area) (PDF 66 KB)

280_2017_3492_MOESM3_ESM.pdf

Prediction corrected visual predictive check (PCVPC). The circles represent the observed data. Dashed red lines depict the 5th and 95th percentiles of the observed concentrations. The solid red line corresponds to the 50th percentiles of the observed concentrations. Shaded blue areas correspond to the 90% CI of the 5th and 95th percentiles of simulated data and shaded red area to the 90% CI of the median of simulated data (PDF 141 KB)

Supplementary material 2 (DOCX 34 KB)

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Völler, S., Pichlmeier, U., Zens, A. et al. Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 81, 305–314 (2018). https://doi.org/10.1007/s00280-017-3492-5

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  • DOI: https://doi.org/10.1007/s00280-017-3492-5

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