Skip to main content
SpringerLink
Log in

Use of etoposide in patients with organ dysfunction: pharmacokinetic and pharmacodynamic considerations

  • Session 2: Pharmacology: Preclinical and Phase I Studies of Topoisomerase Dosing Concepts
  • Etoposide, Pharmacokinetics, Pharmacodynamics
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Etoposide is a podophyllotoxin deriverative with activity against a wide variety of malignancies. It is also used in many clinical conditions in which renal or hepatic function is impaired. To establish a basis for making initial dose adjustments in patients with renal or hepatic dysfunction, the clinical pharmacology (e.g., absorption, distribution, protein binding, metabolism, and elimination) of etoposide is presented. Studies of the use of etoposide in patients with renal or hepatic dysfunction are summarized. The importance of protein binding to etoposide disposition, especially in patients with hepatic dysfunction is discussed. Pharmacodynamics refers to the relationship between drug concentration at the site of action (receptor) and pharmacologic response (toxicity or efficacy). The pharmacodynamics of etoposide has been studied in only a few patients with renal and (or) hepatic dysfunction and must be studied in larger populations before definitive dosing guidelines can be recommended. However, some general initial dosing recommendations for the use of etoposide in patients with renal and hepatic dysfunction are presented.

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. Arbuck SG, Douglass HO, Crom WR, et al. (1986) Etoposide pharmacokinetics in patients with normal and abnormal organ function. J. Clin Oncol 4: 1690–1695

    Google Scholar 

  2. Bennett CL, Sinkule JA, Schilsky RL, Senekjian E, Choi KE (1987) Phase I clinical and pharmacological study of 72-hour continuous infusion of etoposide in patients with advanced cancer. Cancer Res 47:1952–1956

    Google Scholar 

  3. Bennett WM (1988) Guide to drug dosage in renal failure. Clin Pharmacokinet 15: 326–354

    Google Scholar 

  4. Blaschke TF (1977) Protein binding and kinetics of drugs in liver diseases. Clin Pharmacokinet 2: 32–44

    Google Scholar 

  5. Brindley CJ, Antoniw P, Newlands ES, Bagshawe KD (1985) Pharmacokinetics and toxicity of the epipodophyllotoxin derivative etoposide (VP 16-213) in patients with gestational choriocarcinoma and malignant teratoma. Cancer Chemother Pharmacol 15: 66–71

    Google Scholar 

  6. Brouwer KLR, Dukes GE, Powell JR (1992) Influence of liver function on drug disposition. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Vancouver, Washington, p 6-1–6-59

    Google Scholar 

  7. Brunner KW, Sonntag RW, Ryssel HJ (1976) Comparison of the biologic activity of VP-16-213 given IV and orally in capsules or drink ampules. Cancer Treat Rep 60: 1377–1380

    Google Scholar 

  8. Christensen ML, Stewart CF, Crom WR (1989) Evaluation of aminoglycoside disposition in patients previously treated with cisplatin. Ther Drug Monit 11: 631–636

    Google Scholar 

  9. Colombo T, D'Incalci M, Donelli MG, et al (1985) Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver. Xenobiotica 15: 343–350

    Google Scholar 

  10. Crom WR, Pratt CB, Green AA, et al (1984) The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate. J Clin Oncol 2: 655–661

    Google Scholar 

  11. D'Incalci M, Farina P, Sessa C (1982) Pharmacokinetics of VP16-213 given by different administration methods. Cancer Chemother Pharmacol 7: 141–145

    Google Scholar 

  12. D'Incalci M, Rossi C, Zucchetti M, et al (1986) Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res 46: 2566–2571

    Google Scholar 

  13. Evans WE, Sinkule JA, Crom WR (1982) Pharmacokinetics of teniposide (VM26) and etoposide in children with cancer. Cancer Chemother Pharmacol 7: 147–150

    Google Scholar 

  14. Fleming RA, Miller AA, Stewart CF (1989) Etoposide: an update. Clin Pharm 8: 274–293

    Google Scholar 

  15. Fleming RA, Evans WE, Arbuck SG, Stewart CF (1992) Factors affecting in vitro protein binding of etoposide in humans. J Pharm Sci 81: 259–264

    Google Scholar 

  16. Fleming RA, Arbuck SG, Stewart CF (1991) Interspecies differences in in vitro etoposide plasma protein binding. Biochem Pharmacol 42: 2246–2249

    Google Scholar 

  17. Greco FA (1992) Etoposide: seeking the best dose and schedule. Semin Oncol 19: 59–63

    Google Scholar 

  18. Hande KR, Wedlund PJ, Noone RM, Wilkinson GR, Greco FA, Wolff SN (1984) Pharmacokinetics of high-dose etoposide (VP-16-213) adminstered to cancer patients. Cancer Res 44: 379–382

    Google Scholar 

  19. Hande KR, Anthony L, Hamilton R, Bennett R, Sweetman B, Branch R (1988) Identification of etoposide glucuronide as a major metabolite of etoposide in the rat and rabbit. Cancer Res 48: 1829–1834

    Google Scholar 

  20. Hande KR, Bennett R, Hamilton R, Grote T, Branch R (1988) Metabolism and excretion of etoposide in isolated, perfused rat liver model. Cancer Res 48: 5692–5695

    Google Scholar 

  21. Hande KR, Wolff SN, Greco FA, Hainsworth JD, Reed G, Johnson DH (1990) Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 8: 1101–1107

    Google Scholar 

  22. Hande KR, Krozely MG, Greco FA, Hainsworth JD, Johnson DH (1993) Bioavailability of low-dose oral etoposide. J Clin Oncol 11: 374–377

    Google Scholar 

  23. Holthuis JJM, Van de Vyver FL, Oort WJ van, Verleun H, Bekaert AB, De Broe ME (1985) Pharmacokinetic evaluation of increasing dosages of etoposide in a chronic hemodialysis patient. Cancer Treat Rep 69: 1279–1282

    Google Scholar 

  24. Holthuis JJM, Postmus PE, Oort WJ van (1986) Pharmacokinetics of high dose etoposide (VP16-213). Eur J Cancer Clin Oncol 22: 1149–1155

    Google Scholar 

  25. Joel S, Clark P, Slevin M (1991) Renal function and etoposide pharmacokinetics: is dose modification necessary? Proc Am Soc Clin Oncol 10: 103

    Google Scholar 

  26. Lowis SP, Pearson ADJ, Newell DR, Cole M (1993) Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation. Cancer Res 53: 4881–4889

    Google Scholar 

  27. Matzke GR, Millikin SP (1992) Influence of renal function and dialysis on drug disposition. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Vancouver, Washington, p 8-1–8-49

    Google Scholar 

  28. McDermott DF, Galindo A, Sherman RL, Jaffe EA, Coleman M, Pasmantier MW (1987) Inadequacy of predicted creatinine clearance as guide to chemotherapy. Cancer Treat Rep 71: 1067–1069

    Google Scholar 

  29. Melamed AJ, Vanamee P (1988) Estimating creatinine clearance in patients with cancer. Hosp Pharm 23: 898–901

    Google Scholar 

  30. Mick R, Ratain MJ (1991) Modeling interpatient pharmacodynamic variability of etoposide. J Natl Cancer Inst 83: 1560–1564

    Google Scholar 

  31. Miller AA, Stewart CF, Tolley EA (1990) Clinical pharmacodynamics of continuous-infusion etoposide. Cancer Chemother Pharmacol 25: 361–366

    Google Scholar 

  32. Morritu L, Earl HM, Souhami RL, et al (1989) Patients at risk of chemotherapy-associated toxicity in small cell lung cancer. Br J Cancer 59: 801–804

    Google Scholar 

  33. O'Dwyer PJ, LaCreta FP, Daugherty JP et al (1991) Phase I pharmacokinetic study of intraperitoneal etoposide. Cancer Res 51: 2041–2046

    Google Scholar 

  34. Pfluger KH, Schmidt L, Merkel M, Jungclas H, Havemann K (1987) Drug monitoring of etoposide (VP 16-213): correlation of pharmacokinetic parameters to clinical and biochemical data from patients receiving etoposide. Cancer Chemother Pharmacol 20: 59–66

    Google Scholar 

  35. Pfluger KH, Hahn M, Holz JB, et al (1993) Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters and clinical conditions. Cancer Chemother Pharmacol 31: 350–356

    Google Scholar 

  36. Ratain MJ, Schilsky RL, Choi KE, et al (1989) Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 45: 226–233

    Google Scholar 

  37. Ratain MJ, Schilsky RL, Conley BA, Egorin MJ (1990) Pharmacodynamics in cancer therapy. J Clin Oncol 8: 1739–1753

    Google Scholar 

  38. Relling MV, Evans R, Dass C, Desiderio DM, Nemec J (1992) Human cytochrome P450 metabolism of teniposide and etoposide. J Pharmacol Exp Ther 261: 491–496

    Google Scholar 

  39. Rodman JH, Abromowitch M, Sinkule JA (1987) Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J Clin Oncol 5: 1007–1014

    Google Scholar 

  40. Schwinghammer TL, Fleming RA, Rosenfield CS, et al (1993) Disposition of total and unbound etoposide following high-dose therapy. Cancer Chemother Pharmacol 32: 273–278

    Google Scholar 

  41. Sinkule JA, Hutson P, Hayes FA, Etcubanas E, Evans WE (1984) Pharmacokinetics of etoposide (VP-16) in children and adolescents with refractory solid tumors. Cancer Res 44: 3109–3113

    Google Scholar 

  42. Slevin ML, Clark PI, Joel SP, et al (1989) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7: 1333–1340

    Google Scholar 

  43. Stewart CF, Pieper JA, Arbuck SG, Evans WE (1989) Altered protein binding of etoposide in patients with cancer. Clin Pharmacol Ther 45: 49–55

    Google Scholar 

  44. Stewart CF, Arbuck SG, Fleming RA, Evans WE (1990) Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8: 1874–1879

    Google Scholar 

  45. Stewart CF, Fleming RA, Arbuck SG, Evans WE (1990) Prospective evaluation of a model for predicting etoposide plasma protein binding in cancer patients. Cancer Res 50: 6854–6856

    Google Scholar 

  46. Stewart CF, Arbuck SG, Fleming RA, Evans WE (1991) Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther 50: 385–393

    Google Scholar 

  47. Stewart CF, Fleming RA, Madden T (1991) Chemotherapy drugs. In: Schrier RW, Gambertoglio JG (eds) Handbook of drug therapy in liver and kidney disease. Little, Brown, Boston, pp 156–179

    Google Scholar 

  48. Stewart DJ, Nundy D, Maroun JA, Tetreault L, Prior J (1985) Bioavailability, pharmacokinetics, and clinical effects of an oral preparation of etoposide. Cancer Treat Rep 69: 269–273

    Google Scholar 

  49. Tsubaki T, Goodin S, Leader WG, Chandler MHH (1993) Estimation of creatinine clearance in patients with gynecologic cancer. Clin Pharm 12: 685–690

    Google Scholar 

  50. Wolff SN, Grosh WW, Prater K (1987) In vitro pharmacodynamic evaluation of VP-16-213 and implications for chemotherapy. Cancer Chemother Pharmacol 19: 246–249

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, P. O. Box 318, 38101-0318, Memphis, TN, USA

    Clinton F. Stewart

  2. The Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee, Memphis, Tennessee, USA

    Clinton F. Stewart

Authors
  1. Clinton F. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported in part by USPHS Childhood Cancer Center grant CA-23099, Cancer Center Support (CORE) grant CA-21765, a Center of Excellence grant from the State of Tennessee, and American Lebanese Syrian Associated Charities (ALSAC)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stewart, C.F. Use of etoposide in patients with organ dysfunction: pharmacokinetic and pharmacodynamic considerations. Cancer Chemother. Pharmacol. 34 (Suppl 1), S76–S83 (1994). https://doi.org/10.1007/BF00684868

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00684868

Key words

Search

Navigation