Phase I and pharmacokinetic studies of PNU-159548, a novel alkycycline, administered intravenously to patients with advanced solid tumours.
Eur J Cancer
; 38(18): 2407-15, 2002 Dec.
Article
em En
| MEDLINE
| ID: mdl-12460785
ABSTRACT
PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) is the lead compound of a novel class of cytotoxic agents (alkycyclines) with a unique mechanism of action combining DNA intercalation with alkylation of guanines in the DNA major groove. The objectives of two phase I studies were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of PNU-159548 and its active metabolite PNU-169884 when administered intravenously (i.v.) over 10 or 60 min to patients with advanced solid tumours. Patients were treated with escalating doses of PNU-159548, courses repeated every 21 days at doses ranging from 1.0 to 16 mg/m(2). For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. 69 patients received a total of 161 courses. The MTD was reached at 14 and 16 mg/m(2) in heavily (HP) and minimally pretreated/non-pretreated (MP) patients, respectively, with thrombocytopenia as the DLT. A hypersensitivity reaction was observed in 8 patients across all dose levels, characterised by fever with chills, erythema, facial oedema and dyspnoea. The PKs of PNU-159548 and PNU-169884 were linear over the dose range studied. A significant correlation was observed between the percentage decrease in platelet count and the AUC of PNU-159548. In these studies, the DLT of PNU-159548 was thrombocytopenia. The recommended dose for phase II studies of PNU-159548 is 12 and 14 mg/m(2) administered i.v. over 10 min, once every 21 days, in HP and MP patients, respectively.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Daunorrubicina
/
Antibióticos Antineoplásicos
/
Neoplasias
Tipo de estudo:
Etiology_studies
Limite:
Adult
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Aged
/
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Eur J Cancer
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Holanda