Tanespimycin pharmacokinetics: a randomized dose-escalation crossover phase 1 study of two formulations

This crossover phase 1 study compared the pharmacokinetics and safety of tanespimycin, an HSP90 inhibitor, when administered as a suspension for injection and tanespimycin injection, a Cremophor-based formulation.

Two sequential dose groups (275 mg/m(2) [n = 5] and 340 mg/m(2) [n = 12]) were randomized to first receive tanespimycin as a suspension or Cremophor-based formulation infusion followed 7 days later by the other formulation. Serial blood samples were collected over a 24-h period on days 1 and 8 to measure pharmacokinetics of tanespimycin and its major metabolite 17-AG. Patients completing the crossover phase continued treatment with the suspension formulation twice weekly for 2 out of 3 weeks.

Estimates for tanespimycin CLT (12.76 to 17.28 L/h/m(2)), Vz (69.54 to 78.51 L/m(2)) and t1/2 (3 to 4 h) were consistent across doses and formulations. AUC ratio of 17-AG to tanespimycin was approximately 60% in the 275 mg/m(2) treatment arm and 93% to 117% in the 340 mg/m(2) treatment arm. For the 340 mg/m(2) treatment arm, AUC(INF) was similar between both formulations; Cmax was 17% lower for the suspension versus the injection formulation. The most common adverse events were diarrhea, nausea, vomiting, dizziness, headache, fatigue, and elevated aspartate aminotransferase. Drug-related myelosuppression was not observed. The best response was stable disease in 7 of 11 evaluable patients.

The pharmacokinetics of tanespimycin and its major metabolite 17-AG were similar for the tanespimycin suspension for injection and the tanespimycin injection, a Cremophor-containing product. Tanespimycin was well tolerated when administered as a suspension formulation.