Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia:: Comparison of different days, cycles and doses

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration time-curve (AUC) from t=0 to infinite was in average 3.2 hr*mug/ml for the first cycle, and decreased by 17% in four days (P<0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dose-corrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend <0.01). Data suggest accelerated metabolism and elimination of chlorambucil and phenylacetic acid mustard, but reduced oral bioavailability of chlorambucil cannot be excluded. However, except for AUG, none of the pharmacokinetic parameters of chlorambucil changed significantly during the first 4-day treatment period. The maximal plasma concentration and AUC of phenylacetic acid mustard did not change significantly during repeated treatment cycles. According to this trial a dose adjustment of chlorambucil is not necessary during a short-term course, but may be necessary when treatment cycles are repeated. An average increase in the chlorambucil dose of 10% per cycle maintains similar plasma concentration of chlorambucil.