Background: As imatinib pharmacokinetics are highly variable,
plasma levels differ largely between patients under the same dosage.
Retrospective studies in chronic myeloid leukemia (CML) patients
showed significant correlations between low levels and suboptimal
response, and between high levels and poor tolerability. Monitoring of
plasma levels is thus increasingly advised, targeting trough
concentrations of 1000 μg/L and above.
Objectives: Our study was launched to assess the clinical usefulness
of systematic imatinib TDM in CML patients. The present preliminary
evaluation questions the appropriateness of dosage adjustment
following plasma level measurement to reach the recommended trough
level, while allowing an interval of 4-24 h after last drug intake for blood
sampling.
Methods: Initial blood samples from the first 9 patients in the
intervention arm were obtained 4-25 h after last dose. Trough levels
in 7 patients were predicted to be significantly away from the target
(6 <750 μg/L, and 1 >1500 μg/L with poor tolerance), based on a
Bayesian approach using a population pharmacokinetic model.
Individual dosage adjustments were taken up in 5 patients, who had a
control measurement 1-4 weeks after dosage change. Predicted
trough levels were confronted to anterior model-based extrapolations.
Results: Before dosage adjustment, observed concentrations
extrapolated at trough ranged from 359 to 1832 μg/L (median 710;
mean 804, CV 53%) in the 9 patients. After dosage adjustment they
were expected to target between 720 and 1090 μg/L (median 878;
mean 872, CV 13%). Observed levels of the 5 recheck measurements
extrapolated at trough actually ranged from 710 to 1069 μg/L (median
1015; mean 950, CV 16%) and had absolute differences of 21 to 241
μg/L to the model-based predictions (median 175; mean 157, CV 52%).
Differences between observed and predicted trough levels were larger
when intervals between last drug intake and sampling were very short
(~4 h).
Conclusion: These preliminary results suggest that TDM of imatinib
using a Bayesian interpretation is able to bring trough levels closer to
1000 μg/L (with CV decreasing from 53% to 16%). While this may
simplify blood collection in daily practice, as samples do not have to be
drawn exactly at trough, the largest possible interval to last drug intake
yet remains preferable. This encourages the evaluation of the clinical
benefit of a routine TDM intervention in CML patients, which the
randomized Swiss I-COME study aims to.