Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin

Charles Erlichman, Malcolm Moore, Jake J. Thiessen, Ian G. Kerr, Scott Walker, Phyllis Goodman, Georg Bjarnason, Carlo DeAngelis, Peter Bunting

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Abstract

We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 μg/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 μg/kg/ min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 μmol/liter at the initiation of the infusion to a median of 40.4 μmol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/ kg. The area under the concentration × time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.

Original languageEnglish (US)
Pages (from-to)4837-4842
Number of pages6
JournalCancer Research
Volume53
Issue number20
StatePublished - Oct 15 1993
Externally publishedYes

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Doxorubicin
Cyclosporine
Pharmacokinetics
Area Under Curve
Maximum Tolerated Dose
Creatinine
Small Cell Lung Carcinoma
Neutropenia
Bilirubin
Bone Marrow Cells
Thrombocytopenia
Nausea
Vomiting
Half-Life
Stem Cells
Breast Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Erlichman, C., Moore, M., Thiessen, J. J., Kerr, I. G., Walker, S., Goodman, P., ... Bunting, P. (1993). Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin. Cancer Research, 53(20), 4837-4842.

Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin. / Erlichman, Charles; Moore, Malcolm; Thiessen, Jake J.; Kerr, Ian G.; Walker, Scott; Goodman, Phyllis; Bjarnason, Georg; DeAngelis, Carlo; Bunting, Peter.

In: Cancer Research, Vol. 53, No. 20, 15.10.1993, p. 4837-4842.

Research output: Contribution to journalArticle

Erlichman, C, Moore, M, Thiessen, JJ, Kerr, IG, Walker, S, Goodman, P, Bjarnason, G, DeAngelis, C & Bunting, P 1993, 'Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin', Cancer Research, vol. 53, no. 20, pp. 4837-4842.
Erlichman C, Moore M, Thiessen JJ, Kerr IG, Walker S, Goodman P et al. Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin. Cancer Research. 1993 Oct 15;53(20):4837-4842.
Erlichman, Charles ; Moore, Malcolm ; Thiessen, Jake J. ; Kerr, Ian G. ; Walker, Scott ; Goodman, Phyllis ; Bjarnason, Georg ; DeAngelis, Carlo ; Bunting, Peter. / Phase I pharmacokinetic study of cyclosporin a combined with doxorubicin. In: Cancer Research. 1993 ; Vol. 53, No. 20. pp. 4837-4842.
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N2 - We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 μg/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 μg/kg/ min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 μmol/liter at the initiation of the infusion to a median of 40.4 μmol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/ kg. The area under the concentration × time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.

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