PHARMACOKINETICS OF ARA-CMP-STEARATE (YNK01) - PHASE-I STUDY OF THE ORAL ARA-C DERIVATIVE

Ara-CMP-Stearate ta-D-arabinofuranosylcytosine-5'-stearylphosphate, YN K 01, Fosteabine) is the orally applicable prodrug of cytosine-arabino side (Ara-C). During a phase l study in patients with advanced low-gra de non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokineti c parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Fran kfurt, Germany) were determined by HPLC analysis. Seventy-two hours af ter a first starting dose which served for the determination of baseli ne pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a d ose of 100 mg/day and was escalated in subsequent patients to 200 mg/d ay and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate , Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six p atients have been treated with 200 mg/day and another six with was tre ated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one -compartment model, the following pharmacokinetic parameters were obta ined (average and variation coefficient VC). Ara-CMP-Stearate dose-ind ependent parameters: lag time = 1.04 h (0.57); t(max) = 5.72 h (0.30); t(1/2) = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 10 99 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml ( 0.59). The long lag time and late t(max) can be explained by resorptio n in the distal part of the small intestine. No Ara-CMP-Stearate was d etected in urine samples (limit of detection = 500 pg/ml). Pharmacokin etic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t(1/2) = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemol ysis after intravenous administration, it was not possible to determin e its bioavailability by comparing the AUC after oral and i.v. applica tion. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application. This approach allowed us to estimate that an average of 1 5.8% of Ara-CMP-Stearate (VC 0.82) had undergone resorption and final metabolism to Ara-U. The observed half-lives for Ara-C (t(1/2) = 24.4 h, VC = 0.39) and Ara-U (t(max) = 22.0 h, VC = 0.35) after Ara-CMP-Ste arate administration were substantially longer than those after i.v. a pplication of Ara-C, suggesting a prolonged release of Ara-C from the prodrug due to a slow hepatic metabolism Of Ara-CMP-Stearate. These da ta show that Ara-CMP-Stearate is able to maintain prolonged Ara-C plas ma levels and suggest that Ara-C concentrations as in low-dose and pro bably in standard-dose Ara-C therapy can be achieved by oral applicati on of Ara-CMP-Stearate.