Pharmacokinetics of Ara-CMP-Stearate (YNK01) — Phase I Study of the Oral Ara-C Derivative

Abstract

Ara-CMP-Stearate (1-beta-D-Arabino-furanosylcytosine-5′-stearylphosphate, YNK 01, Fosteabine) is an the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a recently started phase-I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, FRG) were determined by HPLC analysis. 72 hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Srearate was administered over 14 days by once daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/d and was escalated in subsequent patients to 200 mg/d, 300 mg/d and 600 mg/d. Plasma and urine concentratiions of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 hours after the end of the 14 day treatment cycle. So far six patients have been treated with 100 mg/d, three with 200 mg/d and another six with 300 mg/d. One patient was treated 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 obtained (average and variation coefficient VC). Ara-CMP-Stearate dose independent 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 = 1099 ng·ml/h (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_max can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500pg/ml). Pharmacokinetcic parameters of ARA-C following Ara-CMP-Stearate application showed the following characteristics: t_1/2 = 24.3 h (0.39), AUC (100mg) = 262 ng·h/ml (0.93), AUC (200mg) = 502 ng·h/ml (0.87), AUC (300mg) = 898 ng·h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after i.v. administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. 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 to estimate that an average of 15.8% of Ara-CMP-Stearate (VC 0.82) had undergone resorption and final metabolism to ARA-U. The observed half lifes for ARA-C(t_1/2 = 24,4h, VC = 0,39) and Ara-U (t_1/2 = 22,0 h, VC = 0,35) after Ara-CMP-Stearate administration were substantially longer than those after intravenous application of Ara-C suggesting a prolonged release of Ara-C from the prodrug due to a slow hepatic metabolism of Ara-CMP-Stearate. These data show that Ara-CMP-Stearate is able to maintain prolonged ARA-C plasma levels and suggest that ARA-C concentrations as in low dose and probably in standard dose ARA-C therapy can be achieved by oral application of Ara-CMP-Stearate.