Pharmacokinetics and Dosage Reduction of c/s-Diammine(1, 1-cyclobutanedicarboxylato)platinum in Patients with Impaired Renal Function

Merrill J. Egorin, Eve A. Olman, David A. Van Echo, Stuart J. Tipping, Margaret Y. Whitacre, Joseph Aisner, Bruce W. Thompson

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296 Scopus citations

Abstract

c/s-Diammine(1, 1-cyclobutanedicarboxylato)platinum (CBDCA) is a nonnephrotoxic but myelosuppressive analogue of cisplatin (DDP) with greatly reduced protein binding and greatly increased renal excretion. Thus, CBDCA might produce undue toxicity in patients with decreased renal function. Twenty-two patients [14 females and 8 males; median age, 66 (range, 35 to 83); median Kamofsky performance status, 70 (range, 40 to 90)] with refractory tumors and renal dysfunction [creatinine clearance (Co) 6 to 83 ml/min] were treated with 31 courses of i.v. bolus CBDCA every 4 to 5 weeks. Dosages were determined by pretreatment Co. Patients with Co ≥40 ml/min received 400 mg/sq m; patients with Co 20 to 39 ml/min received 250 mg/sq m; and patients with Co 0 to 19 ml/min received 150 mg/sq m. Toxicities were assessed by weekly clinical and laboratory assessment. Responses were assessed in patients with measurable disease. Plasma pharmacokinetics and urinary excretion of total and ultrafilterable platinum were measured with flameless atomic absorption spectrometry. Observed toxicities were similar to those in patients with normal renal function. Myelosuppres-sion, especially thrombocytopenia, was the major toxicity. Nausea and vomiting were mild to moderate. There was no ototoxicity, neurotoxicity, or nephrotoxicity or reduction in Co due to CBDCA. Total body clearance of ultrafilterable platinum correlated highly with Co. The percentage of reduction in platelet count correlated highly and linearly with the area under the curve (AUC) of plasma-ultrafilterable platinum. However, for any AUC, there was 17% greater platelet reduction in patients who had previously received extensive myelosuppressive chemotherapy than in nonpretreated patients. Since total body clearance is proportional to Co, platelet reduction is proportional to AUC, and total body clearance = dosage/AUC, we have derived an equation to calculate a dosage that will produce a desired reduction in platelet count. Calculations for theoretical patients (both pretreated and nonpretreated) with Co of 100 ml/min produce dosages very close to maximum tolerated dosages derived in actual Phase I trials. The actual clinical utility of these predictive equations must await validation in prospective studies with larger numbers of patients.

Original languageEnglish (US)
Pages (from-to)5432-5438
Number of pages7
JournalCancer Research
Volume44
Issue number11
StatePublished - Nov 1 1984
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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