title: Pharmacokinetics of Ara-CMP-Stearate (YNK01): phase I study of the oral Ara-C derivative.
abstract: 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); tmax = 5.72 h (0.30); t1/2 = 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 tmax 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: t1/2 = 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Internal Medicine, University of Göttingen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schleyer
authors.forename: J
authors.initials: J
authors.lastname: Braess
authors.forename: B
authors.initials: B
authors.lastname: Ramsauer
authors.forename: M
authors.initials: M
authors.lastname: Unterhalt
authors.forename: C
authors.initials: C
authors.lastname: Kaufmann
authors.forename: S
authors.initials: S
authors.lastname: Wilde
authors.forename: M
authors.initials: M
authors.lastname: Schüssler
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D001086:Arabinofuranosyluracil / Q000652:urine; D001088:Arabinonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D003561:Cytarabine / Q000652:urine; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D018709:Statistics, Nonparametric
chemical_list: D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D003561:Cytarabine; D001086:Arabinofuranosyluracil; C061162:1-arabinofuranosylcytosine-5'-stearylphosphate; D003568:Cytidine Monophosphate