TIME-DEPENDENT KINETICS OF TRETINOIN IN CHRONIC MYELOGENOUS LEUKEMIA DURING INTERMITTENT DOSE SCHEDULING - 1 WEEK ON 1 WEEK OFF

Objective: This study investigated the pharmacokinetics of tretinoin d uring alternating cycles of 1 week of tretinoin treatment and 1 week d rug-free in patients with Ph1+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated w ith tretinoin 80 mg/m(2)/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Bod y systemic exposure to tretinoin as determined by the area under the p lasma concentration-time curve (AUC) decreased significantly during th e first week of drug administration, from (mean +/- SD) 678.3 +/- 498. 1 to 258.7 +/- 272.4 mu g/L.h. In about 40% of the patients the declin e in plasma concentrations was greater than or equal to 80%, while 17% of the population did not experience any decline. On day 7 of cycle 1 , the mean apparent oral clearance (CL/F) was 2.6 times the correspond ing value on day 1. After 1 week without tretinoin, the mean AUC on da y I of cycle 2 was lower (down 15%) but not statistically different fr om the corresponding value observed on day I of cycle 1; 62% of patien ts showed an increase in the AUG, which was 40% higher than the corres ponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL /F of tretinoin during a dosage interval were not statistically differ ent from those observed on day 1 of cycle 1 and cycle 2. On all occasi ons the peak plasma concentration (C-max) was strongly correlated to t he corresponding AUG. No significant change in the time to observed C- max (t(max)) and in the elimination half-life (t1/2) was observed duri ng the whole study. These results confirmed that the metabolism of tre tinoin is rapidly up-regulated in CML patients, with Significant decli nes in plasma drug exposure during the first week of drug administrati on. After tretinoin was discontinued, a return to the noninduced state followed a mean time-cycle similar to the induction. The strong decre ase in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic ex traction of tretinoin is the main cause of the marked decline in plasm a drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off t herapy (vs continuous administration), suggests that such a therapeuti c schedule is the most appropriate for the assessment of clinical effi cacy in those pathologies in which its use is suitable.