Measurement of Cremophor EL Following Taxol: Plasma Levels Sufficient to Reverse Drug Exclusion Mediated by the Multidrug-Resistant Phenotype

Webster, Lorraine K.; Linsenmeyer, Martha E.; Millward, Michael; Morton, Carmel G.; Bishop, James F.; Woodcock, David M.

doi:10.1093/jnci/85.20.1685

Cited by 119 publications

(41 citation statements)

References 12 publications

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“…It has been proposed to induce a cell cycle block distinct from that seen with paclitaxel (9) or to reverse the multidrug resistance phenotype (10,11). However, it is uncertain whether the plasma concentration of CrEL attainable during Taxol infusion is relevant in solid tumors (4,12,13). Collectively, the addition of CrEL is closely related with toxicity, inconvenience, less effective biodistribution, and special devices for the administration of paclitaxel.…”

Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Kim

Kim²,

Chung³

et al. 2004

Clinical Cancer Research

722

467

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Purpose:The rationale for developing an alternative paclitaxel formulation concerns Cremophor EL-related side effects, and a novel paclitaxel delivery system might augment its therapeutic efficacy. Genexol-PM is a polymeric micelle formulated paclitaxel free of Cremophor EL. A phase I study was performed to determine the maximum tolerated dosage, dose-limiting toxicities, and the pharmacokinetic profile of Genexol-PM in patients with advanced, refractory malignancies.Experimental Design: Twenty-one patients were entered into the study. Genexol-PM was i.v. administered over 3 h every 3 weeks without premedication. The Genexol-PM dose was escalated from 135 mg/m 2 to 390 mg/m 2 . Results: All of the patients were evaluable for toxicity and response. Acute hypersensitivity reactions were not observed. Neuropathy and myalgia were the most common toxicities. During cycle 1, grade 3 myalgia occurred in 1 patient at 230 and 300 mg/m 2 , respectively. At 390 mg/m 2 , 2 of 3 patients developed grade 4 neutropenia or grade 3 polyneuropathy. Therefore, the maximum tolerated dosage was determined to be 390 mg/m 2 . There were 3 partial responses (14%) among the 21 patients. Of the 3 responders, 2 were refractory to prior taxane therapy. The paclitaxel area under the curve from time 0 to infinity and peak or maximum paclitaxel concentration seemed to increase with escalating dose, except at 230 mg/m 2 , which suggests that Genexol-PM has linear pharmacokinetics. Conclusion:The main dose-limiting toxicities were neuropathy, myalgia, and neutropenia, and the recommended dosage for a phase II study is 300 mg/m 2 . Genexol-PM is believed to be superior to conventional paclitaxel in terms of the obviation of premedication and the delivery of higher paclitaxel doses without additional toxicity.

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Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Kim

Kim²,

Chung³

et al. 2004

Clinical Cancer Research

722

467

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“…Information on the pharmacokinetics of Cremophor EL in patients is limited. A previous paper using a bio-assay reported Cremophor EL levels up to 0.2% (Webster et al, 1993;Rischin et al, 1996). However, our preliminary information using the HPLC assay has revealed that the Cremophor EL levels are much higher (Sparreboom et al, 1996b;Van Tellingen et al, 1996).…”

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confidence: 71%

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

et al. 1999

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Paclitaxel (Taxol) is a potent anticancer drug with proven activity against a number of human solid tumours, including ovarian and breast, non-small-cell lung, and head and neck cancer (Huizing et al, 1995a;Rowinsky et al, 1995). Because of its poor water solubility the drug is formulated in a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) and dehydrated ethanol USP (1:1, v/v; Taxol®). Prior to intravenous (i.v.) administration the drug solution is diluted 5-to 20-fold with saline or 5% dextrose. Patients receiving therapeutic dosages (e.g. 175 mg m -2 ) of paclitaxel (Taxol) receive about 25 ml of Cremophor EL solvent. The non-linear pharmacokinetic behaviour of paclitaxel in patients has been well documented (Huizing et al, 1993;Sonnichsen et al, 1994;Gianni et al, 1995;Kearns et al, 1995;Huizing et al, 1997). Both a reduction in the clearance and an over proportional increase in peak plasma concentration (C max ) of paclitaxel are observed with increasing dosages indicative that both drug elimination and distribution were affected. We have recently shown that the non-linear pharmacokinetics of paclitaxel in mice results from Cremophor EL exclusively, since linear plasma pharmacokinetics occurred when the same dose levels of paclitaxel were administered in a Cremophor EL free drug formulation (Sparreboom et al, 1996b). In patients, administration of paclitaxel in a Cremophor EL free formulation to test if the pharmacokinetics becomes linear is not a feasible option. Indirectly, however, our observations support the idea that Cremophor EL may also be responsible for the non-linear pharmacokinetics in patients provided that the plasma levels of Cremophor EL are in the same range as those observed in mice.In mice, the plasma concentrations of Cremophor EL as established by high-performance liquid chromatography (HPLC) ranged from 0.3 to 2.1% (Sparreboom et al, 1996b). Information on the pharmacokinetics of Cremophor EL in patients is limited. A previous paper using a bio-assay reported Cremophor EL levels up to 0.2% (Webster et al, 1993;Rischin et al, 1996). However, our preliminary information using the HPLC assay has revealed that the Cremophor EL levels are much higher (Sparreboom et al, 1996b;Van Tellingen et al, 1996). To address the issue if Cremophor EL can also be held responsible for the non-linear pharmacokinetics in patients, we have established the pharmacokinetic behaviour of this excipient in patients receiving 135 or 175 mg m -2 of paclitaxel (Taxol) by 3-or 24-h infusions. Because we have previously suggested that alterations in the affinity of paclitaxel toward plasma components might provide an explanation for the nonlinear plasma pharmacokinetics (Sparreboom et al, 1996b), we have now used an in vitro equilibrium dialysis assay and determination of paclitaxel in plasma ultrafiltrate to assess the influence of Cremophor EL on plasma binding of paclitaxel. PATIENTS AND METHODS PatientsThe patients included in this study received paclitaxel formulated in Cremophor EL:Ethanol 1...

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“…Blank plasma was spiked with 1.0 ml ml À1 cremophor EL and run as an inter-assay control. This concentration of cremophor EL caused approximately 50% inhibition of maximum daunorubicin accumulation (Webster et al, 1993). The accuracy of the control was always 475%.…”

Section: Assays For Biologic Activitymentioning

confidence: 82%

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

et al. 2006

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Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCa), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had 450% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.

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Measurement of Cremophor EL Following Taxol: Plasma Levels Sufficient to Reverse Drug Exclusion Mediated by the Multidrug-Resistant Phenotype

Abstract: The efficacy of paclitaxel against some tumors may be aided by its administration in a vehicle solution containing Cremophor in quantities that reach concentrations in the plasma sufficient to reverse multidrug resistance of neoplastic cells.

Cited by 119 publications

References 12 publications

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

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