Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy

Wyndham H. Wilson, Carlos Alberto Jamis-Dow, George Bryant, Frank M. Balis, Raymond W. Klecker, Susan E. Bates, Bruce A. Chabner, Seth M. Steinberg, David R. Kohler, Robert E. Wittes

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Abstract

Purpose: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. Patients and Methods: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. Results: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 μmol/L, respectively. Dexverapamil did not affect the steady-state concentration (C(ss)) of etoposide, but increased the C(ss) of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. Conclusion: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.

Original languageEnglish (US)
Pages (from-to)1985-1994
Number of pages10
JournalJournal of Clinical Oncology
Volume13
Issue number8
DOIs
StatePublished - Jan 1 1995

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Multiple Drug Resistance
Vincristine
Etoposide
Verapamil
Prednisone
Doxorubicin
Cyclophosphamide
Pharmacokinetics
Drug Therapy
Maximum Tolerated Dose
P-Glycoprotein

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wilson, W. H., Jamis-Dow, C. A., Bryant, G., Balis, F. M., Klecker, R. W., Bates, S. E., ... Wittes, R. E. (1995). Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy. Journal of Clinical Oncology, 13(8), 1985-1994. https://doi.org/10.1200/JCO.1995.13.8.1985
Wilson, Wyndham H. ; Jamis-Dow, Carlos Alberto ; Bryant, George ; Balis, Frank M. ; Klecker, Raymond W. ; Bates, Susan E. ; Chabner, Bruce A. ; Steinberg, Seth M. ; Kohler, David R. ; Wittes, Robert E. / Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy. In: Journal of Clinical Oncology. 1995 ; Vol. 13, No. 8. pp. 1985-1994.
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abstract = "Purpose: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. Patients and Methods: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. Results: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 μmol/L, respectively. Dexverapamil did not affect the steady-state concentration (C(ss)) of etoposide, but increased the C(ss) of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. Conclusion: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.",
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Wilson, WH, Jamis-Dow, CA, Bryant, G, Balis, FM, Klecker, RW, Bates, SE, Chabner, BA, Steinberg, SM, Kohler, DR & Wittes, RE 1995, 'Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy', Journal of Clinical Oncology, vol. 13, no. 8, pp. 1985-1994. https://doi.org/10.1200/JCO.1995.13.8.1985

Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy. / Wilson, Wyndham H.; Jamis-Dow, Carlos Alberto; Bryant, George; Balis, Frank M.; Klecker, Raymond W.; Bates, Susan E.; Chabner, Bruce A.; Steinberg, Seth M.; Kohler, David R.; Wittes, Robert E.

In: Journal of Clinical Oncology, Vol. 13, No. 8, 01.01.1995, p. 1985-1994.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy

AU - Wilson, Wyndham H.

AU - Jamis-Dow, Carlos Alberto

AU - Bryant, George

AU - Balis, Frank M.

AU - Klecker, Raymond W.

AU - Bates, Susan E.

AU - Chabner, Bruce A.

AU - Steinberg, Seth M.

AU - Kohler, David R.

AU - Wittes, Robert E.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Purpose: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. Patients and Methods: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. Results: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 μmol/L, respectively. Dexverapamil did not affect the steady-state concentration (C(ss)) of etoposide, but increased the C(ss) of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. Conclusion: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.

AB - Purpose: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. Patients and Methods: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. Results: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 μmol/L, respectively. Dexverapamil did not affect the steady-state concentration (C(ss)) of etoposide, but increased the C(ss) of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. Conclusion: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.

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