PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study.

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score

Determination of FCE 26644, a new polysulphonated derivative of distamycin A, in monkey plasma by reversed-phase ion-pair high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective ion-pair high-performance liquid chromatographic method for the determination of 7,7'-carbonylbis[imino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino]¿- bis(1,3-naphthalenedisulphonic acid), tetrasodium salt in monkey plasma has been developed. The compound and internal standard (bromphenol blue) were extracted from plasma samples were methylene chloride (twice) after deproteination with acetonitrile and addition of the ion-pairing agent (tetrabutylammonium hydroxide). The combined organic phases were dried, the residue dissolved in the mobile phase and then analysed by reversed-phase ion-pair liquid chromatography under isocratic conditions. The HPLC analysis time was about 20 min. Quantitation was achieved by UV detection at 323 nm. The linearity, precision and accuracy of the method were evaluated. The limit of quantitation was 0.3 microgram/ml plasma. No interference from blank monkey, mouse, rat, dog and human plasma was observed. The suitability of the method for in vivo samples was checked by analysis of plasma samples drawn from three male cynomolgus monkeys that had received a 20 mg/kg single i.v. dose of the test compound.

Determination of tallimustine in human plasma by high-performance liquid chromatography.

A sensitive and reproducible HPLC method for the determination of tallimustine (I) in human plasma has been developed and validated. Compound I was extracted from plasma by solid-phase extraction using a C18 cartridge from which the test compound was eluted with a methanol-formic acid mixture. The methanol solution was evaporated to dryness and the residue dissolved in a 0.2 M formic acid in methanol-water (1:1, v/v) mixture, then injected onto the HPLC column. The chromatographic separation was performed isocratically by a reversed-phase column filled with ODS, using a 50 mM KH2PO4-acetonitrile mixture as the mobile phase. The flow-rate was 1 ml/min. The eluate was monitored at 314 nm. No peak interfering with that of I was observed when blank human plasma was assayed. Linearity was established in the concentration range 0.5-85.5 nanograms of I per millilitre of plasma. Four calibration curves in plasma, prepared and run on four different days, showed correlation coefficients higher than 0.99 and good reproducibility of the slope (C.V. = 4.5%). The intra-day precision, evaluated at three concentrations (in the low, mid and high range of the standard curve) and expressed as C.V. ranged from 0.9 to 14.4%. The inter-day precision evaluated at the same concentrations was better than 10.2%. The inter-day accuracy evaluated in the same samples and expressed as the ratio of found/added amount of I, ranged from 86.2 to 108.5%. The limit of quantitation was 0.5 ng/ml plasma. The HPLC method described here was successfully employed for the determination of I in some plasma samples obtained during a phase I clinical trial with the test compound.