Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology

Abstract

In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r = 0.924) over the full range of doses studied (4-36 mg/m2) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1 +/- 7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of greater than 18 mg/m2 and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m2. No response were seen in this patient population.

High Dose Chemotherapy with Thiotepa, Mitoxantrone and Carboplatin (TMJ) Followed by Autologous Stem Cell Support in 100 Consecutive Lymphoma Patients in a Single Centre: Analysis of Efficacy, Toxicity and Prognostic Factors

“…Mitoxantrone was included in the TMJ regimen because it lacks the ability to produce the quinine-type free radicals thought to be responsible for the anthracycline associated cardiac toxicity and its primary dose limiting toxicity is myelosuppression [35,36]. The pharmacokinetics of mitoxantrone is linear with increasing dose [37].…”

Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours

“…In a single agent phase I study in 23 patients , where losoxantrone dose ranging from 5 -55 mg m 72 was administered, the plasma clearance averaged 417+194 ml min m 72 . In another single agent study in 13 patients (Allen et al, 1991), where losoxantrone dose ranged from 4 -36 mg m 72 , the plasma clearance averaged 220+89 ml min m 72 . In the current study where losoxantrone was given with cyclophosphamide, clearance averaged 526+190 ml min m 72 and was linear over the dose range of 30 to 110 mg m 72 .…”

“…Compartmental methods were used to fit losoxantrone concentrations using the software WINNONLIN (Pharsight Corporation, Cary, NC, USA). The pharmacokinetic parameters of losoxantrone from this combination study were compared (however, no statistical comparisons were made between these across study data) with those obtained in two single agent studies (Allen et al, 1991;Graham et al, 1992), and a study where losoxantrone was administered along with paclitaxel (Diab et al, 1999).…”

Structure-activity studies with cytotoxic anthrapyrazoles

“…The dose-limiting toxicity for all three drugs was myelosuppression with leukopenia predominating for losoxantrone and piroxantrone (8)(9)(10)(11), and neutropenia being most important for teloxantrone (12,13). In general, there was no evidence of cardiac toxicity; however, a high incidence of cardiotoxicity was observed in patients receiving high cumulative doses of piroxantrone (1).…”