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Phenotypical difference in deamination of cytarabine is not evident in induction therapy for acute myeloid leukaemia
  1. Mikkel Krogh-Madsen1,
  2. Steen Hansen Honoré2,
  3. Morten Krogh Jensen3,
  4. Ove Juul Nielsen4,
  5. Hannah Søndergaard Jensen1,
  6. Per Hartvig Honoré1
  1. 1Faculty of Health and Medical Sciences, Department of Drug design and Pharmacology, University of Copenhagen, Denmark
  2. 2Faculty of Health and Medical Sciences, Department of Pharmacy, University of Copenhagen, Denmark
  3. 3Department of Haematology L-124, Herlev Hospital, Herlev, Denmark
  4. 4Department of Haematology L-4042, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to Professor Per Hartvig Honoré, Faculty of Health and Medical Sciences, Department of Drug design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; peh{at}sund.ku.dk

Abstract

Objective To investigate the uracil arabinoside/cytarabine (Ara-U/Ara-C) ratios with the lower dose in adult acute myeloid leukaemia (AML) induction therapy (100 mg/m2 Ara-C) where no enzyme saturation is expected.

Methods A precise and robust high-performance liquid chromatography (HPLC) method for simultaneous determination of Ara-C and its main inactive metabolite Ara-U in human plasma was developed and validated. Nineteen patients with acute myeloid leukaemia were treated with Ara-C in a dose of 100 mg/m2 together with daunorubicin and etoposide. Plasma concentrations were used to construct the standard normality plot to indicate towards two different phenotypes for the deamination enzyme. This was confirmed with the Shapiro–Wilks test for normality and a histogram of the distribution of the ratios.

Results The lower limits of quantification (LLoQ) of the developed method were 32 ng/ml and 10 ng/ml for Ara-C and Ara-U, respectively. Precision, accuracy, recovery, selectivity and stability varied by no more than 15% at concentrations above LLoQ and by 20% at LLoQ, except for long-term stability of Ara-U. Both the Shapiro–Wilks test for normality and the histogram showed a unimodal distribution. The non-transformed values of the Ara-U/Ara-C ratios were between 0.3 and 17.7 (median 2.2). No correlations between Ara-U/Ara-C ratios and age, sex, liver or renal function or treatment outcome were found. Fifteen of the 19 patients had complete remission of the disease and 2 had partial remission.

Conclusions Division into slow and fast Ara-C metabolisers in this patient population could not be made and specific dose individualisations can therefore not be recommended.

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