A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors

Ronan Joseph Kelly, Robert W. Robey, Clara C. Chen, Deborah Draper, Victoria Luchenko, Daryl Barnett, Robert K. Oldham, Zinnah Caluag, A. Robin Frye, Seth M. Steinberg, Tito Fojo, Susan E. Bates

Research output: Contribution to journalArticle

Abstract

Background: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods: CBT-1® was dosed at 500 mg/m 2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m 2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC 0-3) was determined for 99mTc-sestamibi. Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56 + PBMCs was a statistically significant 51%-100% lower (p99mTc-sestamibi AUC 0-3 for liver (normalized to the AUC 0-3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p99mTc-sestamibi imaging in a patient before and after receiving CBT-1®. 99mTc-sestamibi scans of the chest were performed at 1, 2, and 3 hours after the administration of sestamibi before (top row) and after (bottom row) 6 days of oral administration of CBT-1®. Greater retention of sestamibi was observed after treatment with CBT-1®. model for Pgp has been lacking, recent studies have exploited a Brca1 -/-; p53 -/- mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.

Original languageEnglish (US)
Pages (from-to)512
Number of pages1
JournalOncologist
Volume17
Issue number4
DOIs
StatePublished - 2012
Externally publishedYes

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P-Glycoprotein
Paclitaxel
Technetium Tc 99m Sestamibi
Area Under Curve
Blood Cells
docetaxel
Neoplasms
Doxorubicin
Pharmacokinetics
Benzylisoquinolines
Rhodamines
ATP-Binding Cassette Transporters
Liver
Neutropenia
Oral Administration
Appointments and Schedules
Thorax
Therapeutics
Animal Models
Breast Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., ... Bates, S. E. (2012). A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. Oncologist, 17(4), 512. https://doi.org/10.1634/theoncologist.2012-0080

A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. / Kelly, Ronan Joseph; Robey, Robert W.; Chen, Clara C.; Draper, Deborah; Luchenko, Victoria; Barnett, Daryl; Oldham, Robert K.; Caluag, Zinnah; Frye, A. Robin; Steinberg, Seth M.; Fojo, Tito; Bates, Susan E.

In: Oncologist, Vol. 17, No. 4, 2012, p. 512.

Research output: Contribution to journalArticle

Kelly, RJ, Robey, RW, Chen, CC, Draper, D, Luchenko, V, Barnett, D, Oldham, RK, Caluag, Z, Frye, AR, Steinberg, SM, Fojo, T & Bates, SE 2012, 'A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors', Oncologist, vol. 17, no. 4, pp. 512. https://doi.org/10.1634/theoncologist.2012-0080
Kelly, Ronan Joseph ; Robey, Robert W. ; Chen, Clara C. ; Draper, Deborah ; Luchenko, Victoria ; Barnett, Daryl ; Oldham, Robert K. ; Caluag, Zinnah ; Frye, A. Robin ; Steinberg, Seth M. ; Fojo, Tito ; Bates, Susan E. / A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. In: Oncologist. 2012 ; Vol. 17, No. 4. pp. 512.
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T1 - A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors

AU - Kelly, Ronan Joseph

AU - Robey, Robert W.

AU - Chen, Clara C.

AU - Draper, Deborah

AU - Luchenko, Victoria

AU - Barnett, Daryl

AU - Oldham, Robert K.

AU - Caluag, Zinnah

AU - Frye, A. Robin

AU - Steinberg, Seth M.

AU - Fojo, Tito

AU - Bates, Susan E.

PY - 2012

Y1 - 2012

N2 - Background: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods: CBT-1® was dosed at 500 mg/m 2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m 2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC 0-3) was determined for 99mTc-sestamibi. Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56 + PBMCs was a statistically significant 51%-100% lower (p99mTc-sestamibi AUC 0-3 for liver (normalized to the AUC 0-3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p99mTc-sestamibi imaging in a patient before and after receiving CBT-1®. 99mTc-sestamibi scans of the chest were performed at 1, 2, and 3 hours after the administration of sestamibi before (top row) and after (bottom row) 6 days of oral administration of CBT-1®. Greater retention of sestamibi was observed after treatment with CBT-1®. model for Pgp has been lacking, recent studies have exploited a Brca1 -/-; p53 -/- mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.

AB - Background: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods: CBT-1® was dosed at 500 mg/m 2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m 2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. 99mTc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC 0-3) was determined for 99mTc-sestamibi. Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56 + PBMCs was a statistically significant 51%-100% lower (p99mTc-sestamibi AUC 0-3 for liver (normalized to the AUC 0-3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p99mTc-sestamibi imaging in a patient before and after receiving CBT-1®. 99mTc-sestamibi scans of the chest were performed at 1, 2, and 3 hours after the administration of sestamibi before (top row) and after (bottom row) 6 days of oral administration of CBT-1®. Greater retention of sestamibi was observed after treatment with CBT-1®. model for Pgp has been lacking, recent studies have exploited a Brca1 -/-; p53 -/- mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.

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