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Titolo:
ORAL CYTARABINE OCFOSFATE IN ACUTE MYELOID-LEUKEMIA AND NON-HODGKINS-LYMPHOMA - PHASE I II STUDIES AND PHARMACOKINETICS/
Autore:
BRAESS J; FREUND M; HANAUSKE A; HEIL G; KAUFMANN C; KERN W; SCHUSSLER M; HIDDEMANN W; SCHLEYER E;
Indirizzi:
UNIV GOTTINGEN,DEPT HEMATOL & ONCOL,ROBERT KOCH STR 40 D-37075 GOTTINGEN GERMANY UNIV ROSTOCK,DEPT HEMATOL & ONCOL ROSTOCK GERMANY UNIV ZIEKENHUIS GASTHUISBERG,DEPT ONCOL LOUVAIN BELGIUM MHH HANNOVER,DEPT HEMATOL & ONCOL HANNOVER GERMANY ASTA MED FRANKFURT GERMANY
Titolo Testata:
Leukemia
fascicolo: 10, volume: 12, anno: 1998,
pagine: 1618 - 1626
SICI:
0887-6924(1998)12:10<1618:OCOIAM>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOSE CYTOSINE-ARABINOSIDE; DRUG-INTERACTIONS; ARA-C; ETA-D-ARABINOFURANOSYLCYTOSINE-5'-STEARYLPHOSPHATE; MITOXANTRONE; METABOLISM; PHARMACOLOGY; INVOLVEMENT; INDUCTION; YNKO1;
Keywords:
PHARMACOKINETICS; ORAL APPLICATION; AML; NHL; CYTOSINE ARABINOSIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
35
Recensione:
Indirizzi per estratti:
Citazione:
J. Braess et al., "ORAL CYTARABINE OCFOSFATE IN ACUTE MYELOID-LEUKEMIA AND NON-HODGKINS-LYMPHOMA - PHASE I II STUDIES AND PHARMACOKINETICS/", Leukemia, 12(10), 1998, pp. 1618-1626

Abstract

Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.)and cannotbe applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 - a lipophilic prodrug of AraC - that is resistant to deoxycytidine deaminase and can be applied orally. In thepresent study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase VII study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m(2) (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m(2) dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions,four partial remissions and three patients with NHL two cases reachedpartial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic phi and subsequent beta-oxydation of YNK01 the released AraC land its deamination product AraU) appeared in the systemic circulation. Timeof maximum concentration (h), half-life (h) and area under the curve (ng . h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1(0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized toAraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m(2) plasma levels of AraC werecomparable to those achieved after low-dose AraC treatment (20 mg/m(2)) while at doses of YNK01 of 450-600 mg/m(2) concentrations of standard-dose AraC (100 mg/m(2)) were obtained. We conclude that YNK01 showsconsiderable activity against relapsed and refractory AML and NHL andthat its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/07/20 alle ore 17:59:21