Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel

Baker, Sharyn D.; Zhao, Ming; Lee, Carlton K. K.; Verweij, Jaap; Zabelina, Yelena; Brahmer, Julie R.; Wolff, Antonio C.; Sparreboom, Alex; Carducci, Michael A.

doi:10.1158/1078-0432.ccr-0842-03

Cited by 114 publications

(103 citation statements)

References 49 publications

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“…Docetaxel PK parameters were consistent with those reported historically despite the co-administration of ispinesib (Figure 2; Baker et al, 2003). …”

Section: Pharmacokineticssupporting

confidence: 84%

“…Using a validated population model, observed ispinesib concentration -time data from this study were overlaid on the simulated profile. Observed docetaxel data from subjects in this study administered 60 and 75 mg m À2 were overlaid with historical data from subjects dosed with 35, 75 and 100 mg m À2 docetaxel (Baker et al, 2003) to ascertain if an interaction was observed affecting docetaxel concentration -time profiles.…”

Section: Pharmacokineticsmentioning

confidence: 99%

See 1 more Smart Citation

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

et al. 2008

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The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6 -12 mg m À2 ) and docetaxel (50 -75 mg m À2 ). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m À2 with docetaxel 60 mg m À2 . Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (X18 weeks). One patient with HRPC had a confirmed 450% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

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“…Docetaxel PK parameters were consistent with those reported historically despite the co-administration of ispinesib (Figure 2; Baker et al, 2003). …”

Section: Pharmacokineticssupporting

confidence: 84%

Section: Pharmacokineticsmentioning

confidence: 99%

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

et al. 2008

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“…Consistent with this hypothesis is some evidence showing that the level of circulating docetaxel in the first course of treatment is positively related to the time to progression in non-small cell lung cancer patients (20). Since the level was typically reduced to the low nanomolar range by one week after dose administration, docetaxel may have caused a persistent reduction of dynamicity (21). However, the evidence does not suggest that higher dosages of depolymerizing drugs, which affect microtubule integrity rather than dynamicity, are less effective therapeutically (see Discussion).…”

Section: Introductionmentioning

confidence: 69%

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Uppal

Li²,

Wendt³

et al. 2007

Int J Oncol

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Abstract. Subcellular distribution of mass can be analyzed by a technique that involves culturing cells on interferometers and digitizing their interference contours. Contour sampling resulted in 102 variables per cell, which were predictors of oncogenic transformation. Cell phenotypes can be deconstructed by use of latent factors, which represent the covariance of the real variables. The reversal of the cancertype phenotype by a combination of microtubule-stabilizing and -depolymerizing agents was described previously. The implications of these results have been explored by clinicians who treated patients with the combination of docetaxel and vinorelbine (Navelbine ® ). The current study was performed to determine the effects of different combinations on phenotype and in phases of the cell cycle other than mitosis. Combinations of paclitaxel with either colchicine, podophyllotoxin, nocodazole, or vinblastine caused phenotype reversal. Paclitaxel analogue, 7-deoxytaxol, by itself caused reversal. Factors #4, (filopodia), #5 (displacement and/or deep invaginations in the periphery), #8, and #12 took on values typical of normal cells, whereas the values of #7 (p21-activated kinase), and #13 (rounding up) shifted toward the cancer-type. All combinations altered microtubule arrangement at the cell edge. Delivery schedules and drug ratios used in clinical studies were subjected to analysis. Clinical response rates were better when the combination was not interspersed with a single agent (P=0.004). The results support the idea that efficacy depends upon simultaneous exposure to both agents, and suggest a novel mechanism for combination therapies. These therapies appear to restore in transformed cells some of the features of a contactinhibited cell, and to impede progress through the cell cycle even when provided at nanomolar concentrations.

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“…The differences described here may have clinical implications, providing a rational approach to lower the therapeutic concentrations of docetaxel-based chemotherapy. In this sense, at the clinical setting, it has been shown that weekly regimen of docetaxel (with lower concentrations of drug) can achieve a clinical response comparable to traditional 3-weekly regimens (with higher concentrations of drug), although the side effects profile is improved (Baker et al, 2004). In addition, the cytotoxicity of docetaxel mediated by mechanisms alternative to apoptosis may be partly responsible for their efficacy in treating breast cancers, which may be apoptosis deficient.…”

Section: Discussionmentioning

confidence: 99%

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

2006

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Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional profiling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.

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Comparative Pharmacokinetics of Weekly and Every-Three-Weeks Docetaxel

Cited by 114 publications

References 49 publications

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

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