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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Burris
Howard A
HA
The Sarah Cannon Research Institute, 3322 West End Ave, Nashville, TN 37203, USA.
Berman
David
D
Murthy
Bindu
B
Jones
Suzanne
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005079:Excipients; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D013535:Suspensions
C524971:17-amino-17-demethoxygeldanomycin; D000970:Antineoplastic Agents; D016227:Benzoquinones; D005079:Excipients; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D013535:Suspensions; C112765:tanespimycin; C000515:cremophor EL; D005990:Glycerol