The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer

Daniel A. Rushing, Susan R. Raber, Keith A. Rodvold, Stephen C. Piscitelli, Gary S. Plank, Duane A. Tewksbury

Research output: Contribution to journalArticle

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Abstract

Background. The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. Methods. Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine‐modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1‐hour infusion after a 2‐hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high‐pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination halflife (T.50). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. Results. Cyclosporine modulation increased the AUC0‐36 of doxorubicinol by 48% (P = 0.042) and the AUC0‐36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T.50 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0‐36 to the doxorubicin AUC0‐36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug‐related toxicity was also greater with the cyclosporine‐modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubucin (defined by AUC) and the surviving fraction of the leukocyte count (r = ‐0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporinemodulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = ‐0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. Conclusions. The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P‐glycoprotein in normal tissues and to selectively inhibit the cytochrome P‐450 enzyme system. Further study of this potentially significant drugdrug interaction is warranted.

Original languageEnglish (US)
Pages (from-to)834-841
Number of pages8
JournalCancer
Volume74
Issue number3
DOIs
StatePublished - Aug 1 1994

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Small Cell Lung Carcinoma
Doxorubicin
Cyclosporine
Pharmacokinetics
Leukocyte Count
Area Under Curve
Blood Platelets
Aptitude
Myalgia
P-Glycoprotein
Vincristine
Drug-Related Side Effects and Adverse Reactions
Platelet Count
Drug Interactions
Cyclophosphamide
Cytochrome P-450 Enzyme System
Half-Life
Weight Loss

Keywords

  • cyclosporine
  • doxorubicin
  • doxorubicinol
  • lung cancer
  • pharmacokinetics
  • resistance modulation
  • small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. / Rushing, Daniel A.; Raber, Susan R.; Rodvold, Keith A.; Piscitelli, Stephen C.; Plank, Gary S.; Tewksbury, Duane A.

In: Cancer, Vol. 74, No. 3, 01.08.1994, p. 834-841.

Research output: Contribution to journalArticle

Rushing, Daniel A. ; Raber, Susan R. ; Rodvold, Keith A. ; Piscitelli, Stephen C. ; Plank, Gary S. ; Tewksbury, Duane A. / The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. In: Cancer. 1994 ; Vol. 74, No. 3. pp. 834-841.
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title = "The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer",
abstract = "Background. The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. Methods. Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine‐modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1‐hour infusion after a 2‐hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high‐pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination halflife (T.50). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. Results. Cyclosporine modulation increased the AUC0‐36 of doxorubicinol by 48{\%} (P = 0.042) and the AUC0‐36 of doxorubicinol by 443{\%} (P = 0.0001), whereas the doxorubicin clearance declined by 37{\%} (P = 0.0495). No difference was found in the Vss or T.50 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0‐36 to the doxorubicin AUC0‐36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug‐related toxicity was also greater with the cyclosporine‐modulated course of doxorubicin. A 91{\%} reduction in the leukocyte count followed the modified course, compared with an 84{\%} reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubucin (defined by AUC) and the surviving fraction of the leukocyte count (r = ‐0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporinemodulated course (72.8{\%}) than after the initial course (36.4{\%}) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = ‐0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. Conclusions. The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P‐glycoprotein in normal tissues and to selectively inhibit the cytochrome P‐450 enzyme system. Further study of this potentially significant drugdrug interaction is warranted.",
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T1 - The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer

AU - Rushing, Daniel A.

AU - Raber, Susan R.

AU - Rodvold, Keith A.

AU - Piscitelli, Stephen C.

AU - Plank, Gary S.

AU - Tewksbury, Duane A.

PY - 1994/8/1

Y1 - 1994/8/1

N2 - Background. The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. Methods. Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine‐modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1‐hour infusion after a 2‐hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high‐pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination halflife (T.50). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. Results. Cyclosporine modulation increased the AUC0‐36 of doxorubicinol by 48% (P = 0.042) and the AUC0‐36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T.50 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0‐36 to the doxorubicin AUC0‐36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug‐related toxicity was also greater with the cyclosporine‐modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubucin (defined by AUC) and the surviving fraction of the leukocyte count (r = ‐0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporinemodulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = ‐0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. Conclusions. The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P‐glycoprotein in normal tissues and to selectively inhibit the cytochrome P‐450 enzyme system. Further study of this potentially significant drugdrug interaction is warranted.

AB - Background. The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer. Methods. Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine‐modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1‐hour infusion after a 2‐hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high‐pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination halflife (T.50). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices. Results. Cyclosporine modulation increased the AUC0‐36 of doxorubicinol by 48% (P = 0.042) and the AUC0‐36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T.50 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0‐36 to the doxorubicin AUC0‐36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug‐related toxicity was also greater with the cyclosporine‐modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubucin (defined by AUC) and the surviving fraction of the leukocyte count (r = ‐0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporinemodulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = ‐0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias. Conclusions. The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P‐glycoprotein in normal tissues and to selectively inhibit the cytochrome P‐450 enzyme system. Further study of this potentially significant drugdrug interaction is warranted.

KW - cyclosporine

KW - doxorubicin

KW - doxorubicinol

KW - lung cancer

KW - pharmacokinetics

KW - resistance modulation

KW - small cell lung cancer

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