A Phase I Trial of a Potent P-Glycoprotein Inhibitor, Zosuquidar Trihydrochloride (LY335979), Administered Intravenously in Combination with Doxorubicin in Patients with Advanced Malignancy

Sandler, Alan; Gordon, Michael A.; Alwis, Dinesh P. de; Pouliquen, Isabelle; Green, Lisa; Marder, Phil; Chaudhary, Archana; Fife, Karen; Battiato, Linda; Sweeney, Christopher; Jordan, Christopher; Burgess, Michael; Slapak, Christopher A.

doi:10.1158/1078-0432.ccr-03-0644

Cited by 113 publications

(53 citation statements)

References 13 publications

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“…Pharmacokinetic data, from an ongoing study, failed to show any positive correlation between the clearance of zosuquidar and body surface area (11,12). Thus, dosing by body surface area contributed to variability in plasma concentration and potentially to P-glycoprotein inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…In cycle 2 and all of the other cycles, patients received the combination of docetaxel and oral zosuquidar. The initial dose of zosuquidar was based on results of previous Phase 1 studies (11,12).…”

Section: Methodsmentioning

confidence: 99%

“…In dose levels 5 and above, zosuquidar plasma sampling was carried out before the first dose and 1, 2, 2.5, 3, 3.5, 4,5,6,8,12,13,14,15,16,18,20,24, and 30 hours from the time of the first dose in the second cycles. Plasma samples were analyzed with a validated high-performance liquid chromatography/fluorescence detection method over the concentration range 20 ng/mL to 2000 ng/mL as published previously (11).…”

Section: Methodsmentioning

confidence: 99%

“…† Dose-normalized AUC (0-tn) , AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) , and C max are presented. ‡ Zosuquidar orally 100 mg/m 2 every 8 h to 500 mg every 12 h. § T Ͼ 0.2 mol/L is the time above a threshold level of 0.2 mol/L and was not summarized for dose levels 1-4 and 5-7 due to dose reduction in some subjects.…”

Section: Methodsmentioning

confidence: 99%

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Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

Fracasso¹,

Goldstein²,

Alwis³

et al. 2004

Clinical Cancer Research

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Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors.Experimental Design: In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m 2 . Zosuquidar was escalated from 100 to 300 mg/m 2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained. Results: Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m 2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization.Conclusions: Docetaxel at 75 or 100 mg/m 2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

Fracasso¹,

Goldstein²,

Alwis³

et al. 2004

Clinical Cancer Research

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“…Similar findings were observed for zosuquidar. Phase I research with zosuquidar showed that the drug could be administered safely to patients with AML or solid tumors [103,104] . However, a randomized placebo-controlled doubleblind trial in 449 patients with newly diagnosed AML or high-risk myelodysplastic syndrome, showed no improvement in OS, or complete remission (CR) rates of drug treatment combined with zosuquidar [105] .…”

Section: Inhibition Of P-gpmentioning

confidence: 99%

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Jaramillo¹,

Saig²,

Cloos³

et al. 2018

CDR

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P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

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Introduction to Drug Transporters

Leung¹,

Oganesian²

2008

Drug Metabolism Handbook

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A Phase I Trial of a Potent P-Glycoprotein Inhibitor, Zosuquidar Trihydrochloride (LY335979), Administered Intravenously in Combination with Doxorubicin in Patients with Advanced Malignancy

Abstract: ABSTRACT

Cited by 113 publications

References 13 publications

Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

Phase I Study of Docetaxel in Combination with the P-Glycoprotein Inhibitor, Zosuquidar, in Resistant Malignancies

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

Introduction to Drug Transporters

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