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Titolo:
PHARMACOKINETICS OF ARA-CMP-STEARATE (YNK01) - PHASE-I STUDY OF THE ORAL ARA-C DERIVATIVE
Autore:
SCHLEYER E; BRAESS J; RAMSAUER B; UNTERHALT M; KAUFMANN C; WILDE S; SCHUSSLER M; HIDDEMANN W;
Indirizzi:
UNIV GOTTINGEN,ZENTRUM INNERE MED,HAMATOL ONKOL ABT,ROBERT KOCH STR 40 D-37075 GOTTINGEN GERMANY UNIV GOTTINGEN,DEPT INTERNAL MED,DIV HEMATOL & ONCOL W-3400 GOTTINGENGERMANY ASTA MED FRANKFURT GERMANY
Titolo Testata:
Leukemia
fascicolo: 6, volume: 9, anno: 1995,
pagine: 1085 - 1090
SICI:
0887-6924(1995)9:6<1085:POA(-P>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOSE CYTOSINE-ARABINOSIDE; ACUTE MYELOGENOUS LEUKEMIA; MYELODYSPLASTIC SYNDROMES; 1-BETA-D-ARABINOFURANOSYLCYTOSINE; OXIDATION;
Keywords:
ARA-C; PHASE I STUDY; PHARMACOKINETICS; ORAL APPLICATION; FOSTEABINE; CYTOCHROME P450;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
E. Schleyer et al., "PHARMACOKINETICS OF ARA-CMP-STEARATE (YNK01) - PHASE-I STUDY OF THE ORAL ARA-C DERIVATIVE", Leukemia, 9(6), 1995, pp. 1085-1090

Abstract

Ara-CMP-Stearate ta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase l 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 over14 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 200 mg/day and another six with 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 metaboliteof Ara-C was measured during the first 72-h period and after the lastapplication. This approach allowed us to estimate that an average of 15.8% of Ara-CMP-Stearate (VC 0.82) had undergone resorption and finalmetabolism to Ara-U. The observed half-lives for Ara-C (t(1/2) = 24.4h, VC = 0.39) and Ara-U (t(max) = 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 theprodrug 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/07/20 alle ore 18:16:25