Phase I clinical trial and pharmacokinetic evaluation of 4?-0-tetrahydropyranyladriamycin (THP-adriamycin)

Abstract

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m²; for phase II studies using this schedule, a dose of 20 mg/m² weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with α, β, and γ half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, <10% of the compound was eliminated in the urine within 24 h.