Phase I evaluation of carboplatin by use of a dosing strategy based on a targeted area under the platinum concentration-versus-time curve and individual glomerular filtration rate in cats with tumors

Dennis B. Bailey Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Search for other papers by Dennis B. Bailey in
Current site
Google Scholar
PubMed
Close
 DVM
,
Kenneth M. Rassnick Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Search for other papers by Kenneth M. Rassnick in
Current site
Google Scholar
PubMed
Close
 DVM
,
Nathan L. Dykes Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Search for other papers by Nathan L. Dykes in
Current site
Google Scholar
PubMed
Close
 DVM
, and
Lakshmi Pendyala Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263.

Search for other papers by Lakshmi Pendyala in
Current site
Google Scholar
PubMed
Close
 PhD

Abstract

Objective—To determine whether a carboplatin dose calculation that is based on a targeted area under the concentration-versus-time curve (AUCTarget) and individual glomerular filtration rate (GFR) accurately predicts carboplatin-associated myelotoxicoses in tumor-bearing cats, and to determine the maximum tolerated AUCTarget.

Animals—32 cats with tumors.

Procedures—In each cat, plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid was measured to assess GFR. Carboplatin was administered IV. The dose was calculated by use of an equation as follows: Dose = AUCTarget × 2.6 × GFR × body weight. Initial AUCTarget was 2.0 min·mg·mL−1 and was increased in increments of 0.50 min·mg·mL−1 in cohorts of 3 cats. To assess myelotoxic effects, CBCs were performed weekly for ≥ 4 weeks. Following identification of the maximum tolerated AUCTarget, additional cats were treated at that AUCTarget and plasma platinum concentrations were measured in 6 cats.

Results—The AUCTarget values ranged from 2.0 to 3.0 min·mg·mL−1. Neutropenia was the dose-limiting toxicosis, and the maximum tolerated AUCTarget was 2.75 min·mg·mL−1. Nineteen cats received this dose of carboplatin; 13 became neutropenic, but only 1 developed severe neutropenia (< 500 neutrophils/μL), and none had neutropenia-associated clinical signs. In the cats that had plasma platinum concentration determined, the difference between AUCTarget and the measured value ranged from −0.23 to 0.31 min·mg·mL−1 (median, 0.20 min·mg·mL−1).

Conclusions and Clinical Relevance—In cats, carboplatin-associated myelotoxicoses were accurately and uniformly predicted by use of the proposed dosing strategy. The maximum tolerated AUCTarget for a single dose of carboplatin was 2.75 min·mg·mL−1.

Abstract

Objective—To determine whether a carboplatin dose calculation that is based on a targeted area under the concentration-versus-time curve (AUCTarget) and individual glomerular filtration rate (GFR) accurately predicts carboplatin-associated myelotoxicoses in tumor-bearing cats, and to determine the maximum tolerated AUCTarget.

Animals—32 cats with tumors.

Procedures—In each cat, plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid was measured to assess GFR. Carboplatin was administered IV. The dose was calculated by use of an equation as follows: Dose = AUCTarget × 2.6 × GFR × body weight. Initial AUCTarget was 2.0 min·mg·mL−1 and was increased in increments of 0.50 min·mg·mL−1 in cohorts of 3 cats. To assess myelotoxic effects, CBCs were performed weekly for ≥ 4 weeks. Following identification of the maximum tolerated AUCTarget, additional cats were treated at that AUCTarget and plasma platinum concentrations were measured in 6 cats.

Results—The AUCTarget values ranged from 2.0 to 3.0 min·mg·mL−1. Neutropenia was the dose-limiting toxicosis, and the maximum tolerated AUCTarget was 2.75 min·mg·mL−1. Nineteen cats received this dose of carboplatin; 13 became neutropenic, but only 1 developed severe neutropenia (< 500 neutrophils/μL), and none had neutropenia-associated clinical signs. In the cats that had plasma platinum concentration determined, the difference between AUCTarget and the measured value ranged from −0.23 to 0.31 min·mg·mL−1 (median, 0.20 min·mg·mL−1).

Conclusions and Clinical Relevance—In cats, carboplatin-associated myelotoxicoses were accurately and uniformly predicted by use of the proposed dosing strategy. The maximum tolerated AUCTarget for a single dose of carboplatin was 2.75 min·mg·mL−1.

  • 1.

    Theon AP, VanVechten MK, Madewell BR. Intratumoral administration of carboplatin for treatment of squamous cell carcinomas of the nasal plane in cats. Am J Vet Res 1996;57:205210.

    • Search Google Scholar
    • Export Citation
  • 2.

    Fry DR, Snelling SR, Beck C. Partial remission of an inoperable extraskeletal osteosarcoma in association with carboplatin in a cat. Aust Vet Pract 2003;33:103104.

    • Search Google Scholar
    • Export Citation
  • 3.

    Sparkes A, Murphy S, McConnell F, et al. Palliative intracavitary carboplatin therapy in a cat with suspected pleural mesothelioma. J Feline Med Surg 2005;7:313316.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Bailey DB, Rassnick KM, Erb HN, et al. Effect of glomerular filtration rate on clearance and myelotoxicity of carboplatin in cats with tumors. Am J Vet Res 2004;65:15021507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Hahn KA, McEntee MF, Daniel GB, et al. Hematologic and systemic toxicoses associated with carboplatin administration in cats. Am J Vet Res 1997;58:677679.

    • Search Google Scholar
    • Export Citation
  • 6.

    Lund EM, Armstrong PJ, Kirk CA, et al. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Am Vet Med Assoc 1999;214:13361341.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lulich JP, Osborne CA, O'Brien TD, et al. Feline renal failure: questions, answers, questions. Compend Contin Educ Pract Vet 1992;14:127153.

    • Search Google Scholar
    • Export Citation
  • 8.

    Gibaldi M. Introduction to pharmacokinetics. In: Biopharmaceutics and clinical pharmacokinetics. 4th ed. Philadelphia: Lea & Febiger, 1991;113.

    • Search Google Scholar
    • Export Citation
  • 9.

    McClellan JM, Goldstein RE, Erb HN, et al. Effects of administration of fluids and diuretics on glomerular filtration rate, renal blood flow, and urine output in healthy awake cats. Am J Vet Res 2006;67:715722.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Rogers KS, Komkov A, Brown SA, et al. Comparison of four methods of estimating glomerular filtration rate in cats. Am J Vet Res 1991;52:961964.

    • Search Google Scholar
    • Export Citation
  • 11.

    Barthez PY, Chew DJ, DiBartola SP. Effect of sample number and time on determination of plasma clearance of technetium Tc 99m pentetate and orthoiodohippurate sodium I 131 in dogs and cats. Am J Vet Res 2000;61:280285.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Barthez PY, Chew DJ, DiBartola SP. Simplified methods for estimation of 99mTc-pentetate and 131I-orthoiodohippurate plasma clearance in dogs and cats. J Vet Intern Med 2001;15:200208.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Plumb DC. Conversion tables for weight in kilograms to body surface area (m2). In: Plumb's veterinary drug handbook. 5th ed. Ames, Iowa: Blackwell Publishing, 2005;869.

    • Search Google Scholar
    • Export Citation
  • 14.

    Veterinary Co-operative Oncology Group. Veterinary co-operative oncology group—common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats version 1.0. Vet Comp Oncol 2004;2:194213.

    • Search Google Scholar
    • Export Citation
  • 15.

    Dawson B, Trapp RG. Research questions about relationships among variables. In: Basic and clinical biostatistics. 4th ed. New York: Lange Medical Books, 2004;190220.

    • Search Google Scholar
    • Export Citation
  • 16.

    Kisseberth WC, Vail DM, Yaissle J, et al. Phase I clinical evaluation of carboplatin in tumor-bearing cats: a Veterinary Cooperative Oncology Group study. J Vet Intern Med 2008;22:8388.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Price GS, Frazier DL. Use of body surface area (BSA)-based dosages to calculate chemotherapeutic drug dose in dogs: I. Potential problems with current BSA formulae. J Vet Intern Med 1998;12:267271.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Rassnick KM, Moore AS, Northrup NC, et al. Phase I trial and pharmacokinetic analysis of ifosfamide in cats with sarcomas. Am J Vet Res 2006;67:510516.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Mauldin GN, Matus RE, Patnaik AK, et al. Efficacy and toxicity of doxorubicin and cyclophosphamide used in the treatment of selected malignant tumors in 23 cats. J Vet Intern Med 1988;2:6065.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:17481756.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Egorin MJ, Van Echo DA, Tipping SJ, et al. Pharmacokinetics and dosage reduction of cis-diammine(1,1-cyclobutanedicarbo xylato)platinum in patients with impaired renal function. Cancer Res 1984;44:54325438.

    • Search Google Scholar
    • Export Citation
  • 22.

    Siddik ZH, Newell DR, Boxall FE, et al. The comparative pharmacokinetics of carboplatin and cisplatin in mice and rats. Biochem Pharmacol 1987;36:19251932.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Gaver RC, George AM, Duncan GF, et al. The disposition of carboplatin in the beagle dog. Cancer Chemother Pharmacol 1988;21:197202.

  • 24.

    Calvert AH, Harland SJ, Newell DR, et al. Phase I studies with carboplatin at the Royal Marsden Hospital. Cancer Treat Rev 1985;12(suppl A):5157.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Calvert AH, Harland SJ, Newell DR, et al. Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982;9:140147.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Egorin MJ, Van Echo DA, Olman EA, et al. Prospective validation of a pharmacologically based dosing scheme for the cisdiamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum. Cancer Res 1985;45:65026506.

    • Search Google Scholar
    • Export Citation
  • 27.

    Phillips B. Severe, prolonged bone marrow hypoplasia secondary to the use of carboplatin in an azotemic dog. J Am Vet Med Assoc 1999;215:12501252.

    • Search Google Scholar
    • Export Citation
  • 28.

    Miyamoto K. Evaluation of plasma clearance of inulin in clinically normal and partially nephrectomized cats. Am J Vet Res 2001;62:13321335.

  • 29.

    Goy-Thollot I, Chafotte C, Besse S, et al. Iohexol plasma clearance in healthy dogs and cats. Vet Radiol Ultrasound 2006;47:168173.

  • 30.

    Miyamoto K. Evaluation of single-injection method of inulin and creatinine as a renal function test in normal cats. J Vet Med Sci 1998;60:327332.

  • 31.

    Chu E, DeVita VT. Principles of medical oncology. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2005;295306.

    • Search Google Scholar
    • Export Citation

Advertisement