Skip to main content
SpringerLink
Log in

Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m2 per day etoposide equivalent dose infused iv over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, Cmax, and AUC0-∞, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. P. J. O'Dwyer, B. Leyland-Jones, M. T. Alonso, S. Marsoni, and R. E. Wittes. Etoposide (VP-16-213), Current status of an active anticancer drug.New Engl. J. Med. 312:692–699 (1985).

    Article  PubMed  Google Scholar 

  2. M. M. Hudson, H. J. Weinstein, S. S. Donaldson, C. Greenwald, L. Kun, N. J. Tarbell, W. A. Humphrey, C. Rupp, N. M. Marina, J. Wilimas, and M. P. Link. Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.J. Clin. Oncol. 11:1080–1084 (1993).

    CAS  PubMed  Google Scholar 

  3. C. A. Linker, C. A. Ries, L. E. Damon, H. S. Rugo, and J. L. Wolf. Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen.Blood 81:311–318 (1993).

    CAS  PubMed  Google Scholar 

  4. A. M. Gianni, M. Bregni, S. Siena, M. Magni, M. De-Nicola, F. Lombardi, C. Tarella, A. Pileri, and G. Bonadonna. Granulocyte-macrophage colony stimulating factor or granulocyte colony-stimulating factor infusion makes high-dose etoposide a safe outpatient regimen that is effective in lymphoma and myeloma patients.J. Clin. Oncol. 10:1955–1962 (1992).

    CAS  PubMed  Google Scholar 

  5. N. J. Chao, A. S. Stein, G. D. Long, R. S. Negrin, M. D. Amylon, R. M. Wong, S. J. Forman, and K. G. Blume. Busulfan/Etoposide-Initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia.Blood 81:319–323 (1993).

    CAS  PubMed  Google Scholar 

  6. T. L. Schwinghammer, M. Reilly, and C. S. Rosenfeld. Cracking of ABS plastic devices used to infuse undiluted etoposide injection [Letter].Am. J. Hosp. Pharm. 45:1277 (1988).

    CAS  PubMed  Google Scholar 

  7. D. R. Budman, L. N. Igwemezie, S. Kaul, J. Behr, S. Lichtman, P. Schulman, V. Vinciguerra, S. L. Allen, J. Kolitz, K. Hock, K. O'Neill, L. Schacter, and R. H. Barbhaiya. Phase I evaluation of water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.J. Clin. Oncol. 12:1902–1909 (1994).

    CAS  PubMed  Google Scholar 

  8. L. N. Igwemezie, S. Kaul, and R. H. Barbhaiya. Assessment of toxicokinetics and toxicodynamics following intravenous administration of etoposide phosphate in beagle dogs.Pharm. Res. 12:117–123 (1994).

    Article  Google Scholar 

  9. M. J. Milward, D. R. Newell, K. Balmanno, C. J. Charlton, L. Gumbrell, M. J. Lind, F. Chapman, M. Proctor, D. Simmonds, B. Cantwell, G. A. Taylor, C. McDaniel, B. Winograd, and A. H. Calvert. Clinical and pharmacokinetic study of BMY-40481. (Abstract).Proc. Am. Assoc. Cancer Res. 33:529 (1992).

    Google Scholar 

  10. S. Z. Fields, L. N. Igwemezie, S. Kaul, L. P. Schacter, R. J. Schilder, P. P. Litam, B. S. Himpler, C. McAleer, J. Wright, R. H. Barbhaiya, C. J. Langer, and P. O'Dwyer. Phase I study of etoposide phosphate (Etopophos) as a 30-min infusion on days 1, 3, and 5.Clin. Cancer Res. 1:105–111 (1995).

    CAS  PubMed  Google Scholar 

  11. D. S. Thompson, F. A. Greco, A. A. Miller, N. R. Srinivas, L. N. Igwemezie, J. D. Hainsworth, L. P. Schacter, S. Kaul, R. H. Barbhaiya, G. C. Garrow, and K. D. Hande. A phase I study of etoposide phosphate administered as a daily 30-minute infusion for 5 days.Clin. Pharmacol. Ther. 57:499–507 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. M. Gibaldi and D. Perrier.Pharmacokinetics, 2nd ed., Dekker, New York, 1982.

    Google Scholar 

  13. M. Weiss. A general model of metabolite kinetics following intravenous and oral administration of the parent drug.Biopharm. Drug Dispos. 9:159–176 (1988).

    Article  CAS  PubMed  Google Scholar 

  14. G. E. P. Box and D. R. Cox. Analysis of transformations.J. Roy. Stat. Soc. B. 26:211–252 (1964).

    Google Scholar 

  15. D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.J. Pharmacokin. Biopharm. 15:657–680 (1987).

    Article  CAS  Google Scholar 

  16. V. W. Steinijans and D. Hauschke. International harmonization of regulatory bioequivalence requirements.Clin. Res. Reg. Affairs. 10:203–220 (1993).

    Article  Google Scholar 

  17. SAS Institute.SAS User's Guide: Statistics Version 5.18, 5th ed., SAS Institute, Cary, NC, 1985.

    Google Scholar 

  18. B. P. McGrath, R. W. Watts, and D. B. Elmfeldt. Clinical equivalence of two tablet formulations of feldopine: A placebo controlled study of 24-hour blood pressure control and tolerability.Eur. J. Clin. Pharmacol. 49:169–172 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. S. Kaul, L. N. Igwemezie, D. J. Stewart, S. Z. Fields, M. Kosty, N. Levithan, R. Bukowski, D. Gandara, G. Goss, P. O'Dwyer, L. P. Schacter, and R. H. Barbhaiya. Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors.J. Clin. Oncol. 13:2835–2841 (1995).

    CAS  PubMed  Google Scholar 

  20. A. A. Miller, C. F. Stewart, and E. A. Trolley. Clinical pharmacodynamics of continuous infusion etoposide.Cancer Chemother. Pharmacol. 25:361–366 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. C. F. Stewart, S. G. Arbuck, R. A. Fleming, and W. E. Evans. Relationship of systemic exposure to unbound etoposide and hematologic toxicity.Clin. Pharmacol. Ther. 50:385–393 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. M. J. Milward, D. R. Newell, V. Mummaneni, L. N. Igwemezie, K. Balmanno, C. J. Charlton, L. Gumbrell, M. J. Lind, F. Chapman, M. Proctor, D. Simmonds, B. M. J. Cantwell, G. A. Taylor, C. McDaniel, B. Winograd, S. Kaul, R. H. Barbhaiya, and A. H. Calvert. Phase I and pharmacokinetic study of a water soluble etoposide prodrug, etoposide phosphate (BMY-40481).Eur. J. Cancer 13A:2409–2411 (1995).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000, Princeton, New Jersey

    Vanaja Mummaneni, Sanjeev Kaul, Linus N. Igwemezie & Rashmi H. Barbhaiya

  2. Cancer Research Unit, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom, UK

    David R. Newell, David Porter, Huw Thomas & A. Hilary Calvert

  3. Cancer Clinical Research, Bristol-Myers Squibb Pharmaceutical Research Institute, Brussels, Belgium

    Benjamin Winograd

Authors
  1. Vanaja Mummaneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjeev Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linus N. Igwemezie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David R. Newell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huw Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Hilary Calvert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Benjamin Winograd
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rashmi H. Barbhaiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mummaneni, V., Kaul, S., Igwemezie, L.N. et al. Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters. Journal of Pharmacokinetics and Biopharmaceutics 24, 313–325 (1996). https://doi.org/10.1007/BF02353515

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02353515

Key Words

Search

Navigation