Pharmacokinetics of Ara-CMP-Stearate (YNK01) : phase I study of the oral Ara-C derivative
Schleyer, E.; Braess, J.; Ramsauer, B.; Unterhalt, M.; Kaufmann, C.; Wilde, S.; Schüssler, M.; Hiddemann, W.
Leukemia 9(6): 1085-1090
1995
ISSN/ISBN: 0887-6924 PMID: 7596174 Document Number: 442835
Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a 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, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day 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 patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. 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/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 resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic 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 hemolysis after intravenous 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 us 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-lives for Ara-C (t-1/2 = 24.4 h, 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 i.v. 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.