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

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Abstract

Purpose

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/m2 [n = 5] and 340 mg/m2 [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/m2), Vz (69.54 to 78.51 L/m2) 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/m2 treatment arm and 93% to 117% in the 340 mg/m2 treatment arm. For the 340 mg/m2 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.

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Acknowledgments

The authors would like to thank the patients and their families. We would also like to thank Mary Dominiecki, PhD; Anne Lambert, MS; Robert O’Beirne; and Andrew Graham for graphics and editorial assistance. The study was sponsored by Bristol-Myers Squibb (and previously Kosan Biosciences).

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Authors and Affiliations

  1. The Sarah Cannon Research Institute, 3322 West End Ave, Nashville, TN, 37203, USA

    Howard A. Burris III & Suzanne Jones

  2. Bristol-Myers Squibb, Princeton, NJ, USA

    David Berman & Bindu Murthy

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  1. Howard A. Burris III
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  2. David Berman
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Correspondence to Howard A. Burris III.

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Burris, H.A., Berman, D., Murthy, B. et al. Tanespimycin pharmacokinetics: a randomized dose-escalation crossover phase 1 study of two formulations. Cancer Chemother Pharmacol 67, 1045–1054 (2011). https://doi.org/10.1007/s00280-010-1398-6

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  • DOI: https://doi.org/10.1007/s00280-010-1398-6

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