ORAL CYTARABINE OCFOSFATE IN ACUTE MYELOID-LEUKEMIA AND NON-HODGKINS-LYMPHOMA - PHASE I II STUDIES AND PHARMACOKINETICS/

Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamin ation with half-lives ranging from 1 h (i.v.) to 4 h (s.c.)and cannot be applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 - a lipophilic prodrug of AraC - that is r esistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinet ics of YNK01 were evaluated in a phase VII study including patients wi th relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-g rade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cy cles with escalating doses starting with a daily dose of 50 mg/m(2) (e quivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated do se was reached at the 600 mg/m(2) dose level with WHO grade 3-4 diarrh oea as the main toxicity. In the 23 patients with AML two complete rem issions, four partial remissions and three patients with stable diseas e were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pha rmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal pa rt of the small intestine and taken up into hepatocytes. After hepatic phi and subsequent beta-oxydation of YNK01 the released AraC land its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve ( ng . h/ml, at the 1200 mg dose level) were as follows (VC variation co efficient) YNK01: 1.0 (0.58), 10.1(0.43), 12622 (0.65); AraC: 23.2 (0. 57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0. 66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC a nd AraC AUC over the whole dose range tested. AraC was released from h epatocytes over a prolonged period of time resulting in long lasting p lasma levels similar to a continuous i.v. infusion. After administrati on of YNK01 at a dosage of 100-150 mg/m(2) plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m(2) ) while at doses of YNK01 of 450-600 mg/m(2) concentrations of standar d-dose AraC (100 mg/m(2)) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.