A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (Valspodar)

Susan Bates, Min Kang, Beverly Meadows, Susan Bakke, Peter Choyke, Maria Merino, Barry Goldspiel, Isagani Chico, Tom Smith, Clara Chen, Robert Robey, Raymond Bergan, William D. Figg, Tito Fojo

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m2 per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m2 per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever, and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

Original languageEnglish (US)
Pages (from-to)1577-1590
Number of pages14
JournalCancer
Volume92
Issue number6
DOIs
StatePublished - Sep 15 2001
Externally publishedYes

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Vinblastine
P-Glycoprotein
Pharmacokinetics
Intravenous Infusions
valspodar
Rhodamines
Maximum Tolerated Dose
Paresthesia
Multiple Drug Resistance
Ataxia
Constipation
Neutropenia
Biological Availability
Appointments and Schedules
Fever
Lymphocytes
Carcinoma
Kidney

Keywords

  • Drug resistance reversal
  • P-glycoprotein antagonist
  • Pharmacokinetic interaction
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (Valspodar). / Bates, Susan; Kang, Min; Meadows, Beverly; Bakke, Susan; Choyke, Peter; Merino, Maria; Goldspiel, Barry; Chico, Isagani; Smith, Tom; Chen, Clara; Robey, Robert; Bergan, Raymond; Figg, William D.; Fojo, Tito.

In: Cancer, Vol. 92, No. 6, 15.09.2001, p. 1577-1590.

Research output: Contribution to journalArticle

Bates, S, Kang, M, Meadows, B, Bakke, S, Choyke, P, Merino, M, Goldspiel, B, Chico, I, Smith, T, Chen, C, Robey, R, Bergan, R, Figg, WD & Fojo, T 2001, 'A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (Valspodar)', Cancer, vol. 92, no. 6, pp. 1577-1590. https://doi.org/10.1002/1097-0142(20010915)92:6<1577::AID-CNCR1484>3.0.CO;2-H
Bates, Susan ; Kang, Min ; Meadows, Beverly ; Bakke, Susan ; Choyke, Peter ; Merino, Maria ; Goldspiel, Barry ; Chico, Isagani ; Smith, Tom ; Chen, Clara ; Robey, Robert ; Bergan, Raymond ; Figg, William D. ; Fojo, Tito. / A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (Valspodar). In: Cancer. 2001 ; Vol. 92, No. 6. pp. 1577-1590.
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abstract = "BACKGROUND. PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m2 per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m2 per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever, and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.",
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author = "Susan Bates and Min Kang and Beverly Meadows and Susan Bakke and Peter Choyke and Maria Merino and Barry Goldspiel and Isagani Chico and Tom Smith and Clara Chen and Robert Robey and Raymond Bergan and Figg, {William D.} and Tito Fojo",
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T1 - A phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (Valspodar)

AU - Bates, Susan

AU - Kang, Min

AU - Meadows, Beverly

AU - Bakke, Susan

AU - Choyke, Peter

AU - Merino, Maria

AU - Goldspiel, Barry

AU - Chico, Isagani

AU - Smith, Tom

AU - Chen, Clara

AU - Robey, Robert

AU - Bergan, Raymond

AU - Figg, William D.

AU - Fojo, Tito

PY - 2001/9/15

Y1 - 2001/9/15

N2 - BACKGROUND. PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m2 per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m2 per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever, and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

AB - BACKGROUND. PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS. Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS. The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m2 per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m2 per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever, and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS. PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

KW - Drug resistance reversal

KW - P-glycoprotein antagonist

KW - Pharmacokinetic interaction

KW - Renal cell carcinoma

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