Pharmacokinetic-pharmacodynamic relationships between pirarubicin exposure and hematotoxicity: clinical application using only one blood sample.

The objective of the present study was to evaluate the relationship between the pharmacokinetic parameters of pirarubicin and of its metabolite doxorubicin measured in plasma and whole blood, and the hematologic toxicity of this drug, in order to evaluate the predictability of changes in white blood cells (WBC) by single measurement of drug concentrations. This pharmacokinetic-pharmacodynamic relationship was studied in a total of 45 patients with different tumor types treated by combined chemotherapy containing pirarubicin, administered as short infusion (10+/-2 min) at doses ranging from 50 to 90 mg. In 45 courses performed in 24 patients, we established the relationship between the half-product of pirarubicin level in whole blood at the end of the infusion and the duration of this infusion, which represents an estimate of the area under the time x concentration curve (AUC(PIRA,wb,ei) = C(PIRA,wb,ei) x duration of infusion/2), the age of the patients and the relative fall in WBC counts.

[Chemical stability of pirarubicin in its use for continuous infusion].

The aim of this study was to examine the chemical stability of pirarubicin in conditions close to ambulatory continuous infusions (infusor). The analyses were performed using an HPLC method in two infusion fluids (G5% and water), in different conditions of conservation (light and obscurity) and at different temperatures (+35 degrees C and +4 degrees C). The results demonstrated that light did not increase the chemical degradation of pirarubicin in doxorubicin which occurred more rapidly in G5% than in water.

Pharmacokinetics and metabolism of pirarubicin in humans: correlation with pharmacodynamics.

The pharmacokinetic monitoring of anthracycline-containing regimens is warranted because of the important toxicity of these drugs and because pharmacokinetic-pharmacodynamic relationships have been clearly established. We studied the pharmacokinetics of the new anthracycline pirarubicin in 80 courses of treatment performed in 27 patients, using a limited sampling protocol we had previously validated. We observed (for 47 of these courses) a significant correlation between the leucocyte cell kill and the pirarubicin area under the time x concentration curve, but the most significant correlation was obtained using the plasma concentration of doxorubicin, a metabolite of pirarubicin, at the end of the infusion.

A limited sampling strategy for the study of pirarubicin pharmacokinetics in humans.

Pirarubicin (4'-O-tetrahydropyranyldoxorubicin, THP-Adriamycin) is a new anthracycline antibiotic that has recently been developed because its reduced cardiac toxicity is associated with an antitumour efficacy similar to that of doxorubicin. Pirarubicin is characterised by strong haematological toxicity, which has been shown to be correlated with pharmacokinetic parameters, especially the area under the time-concentration curve. To obtain routine pharmacokinetic evaluations of pirarubicin for dose monitoring we developed a limited sampling strategy relying on three blood samples taken at the end of the infusion and at 12 and 24 h post-infusion.

New data on the pharmacokinetics of adriamycin and its major metabolite, adriamycinol.

Twenty-two days after administration by intravenous bolus, of 50 mg of adriamycin to several patients we found concentrations of adriamycin and adriamycinol of the order of 100 pcg/ml. In theory, however, with a terminal half-life of 30 h, the plasma levels of adriamycin and adriamycinol should be close to 0.1 pcg/ml.