PHARMACOKINETICS OF PIROXANTRONE IN A PHASE-I TRIAL OF PIROXANTRONE AND GRANULOCYTE-COLONY-STIMULATING FACTOR

Piroxantrone is an anthrapyrazole derivative with broad antitumor acti vity in vitro. In previous phase I trials, the dose-limiting toxicity of this agent was myelosuppression. Therefore, a phase I and pharmacok inetic study of a 1-h infusion of piroxantrone in combination with gra nulocyte-colony stimulating factor was conducted. In this article, we report the results of the pharmacokinetic analysis. Thirty-seven patie nts were studied over a dosage range of 150 to 555 mg/m2. The plasma e limination of piroxantrone was biexponential with a mean (+/- SD) t1/2 alpha of 3.2 +/- 2.7 min and a mean (+/- SD) t1/2beta of 82 +/- 92 min . Clearance was 840 +/- 230 ml/min/m2. A limited sampling strategy was developed to allow the estimation of total drug exposure (area under the plasma concentration-time curve) from the plasma piroxantrone conc entrations at 30, 60, and 120 min after the start of the infusion. The pharmacokinetic behavior of a presumed piroxantrone metabolite not pr eviously described in plasma was also characterized. Based on in vitro cytotoxicity studies with partially purified extract of this compound , we do not believe that it contributes to the antitumor effects of pi roxantrone at the concentrations observed in plasma. Finally. piroxant rone elimination was linear over the nearly 4-fold dose range studied, indicating that when dose adjustments are made. systemic drug exposur e will remain predictable.