The impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors

Dumez, Herlinde; Louwerens, Marloes; Pawinsky, A.; Planting, A. S. T.; Jonge, M. de; Oosterom, A. Van; Highley, Martin; Guetens, Gunther; Mantel, Marijke A.; Boeck, Gert De; Bruijn, Ernst de; Verweij, Jaap

doi:10.1097/00001813-200207000-00004

Cited by 23 publications

(17 citation statements)

References 11 publications

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“…In a previous phase I study we combined docetaxel with gemcitabine to investigate the pharmacokinetics of both agents [2]. The pharmacokinetics of docetaxel were consistent with single-agent data reported in the literature [3,4], indicating a lack of interference by gemcitabine.…”

Section: Introductionsupporting

confidence: 77%

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

Dumez

Guetens²,

Boeck³

et al. 2005

Anti-Cancer Drugs

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We have performed in vitro incubations of blood from male and female volunteers with gemcitabine and docetaxel alone, and in combination, at different concentration gradients in order to investigate changes in partition between red blood cells (RBCs), total plasma and the free fraction. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by UV detection was used to determine the concentrations of both drugs in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated. The partition ratio of docetaxel varied from 0.02 to 1.44 (mean 0.35), reflecting its relatively low affinity for RBCs, probably because of its high plasma protein binding (more than 98%). For gemcitabine, the partition ratio varied from 1 to 5, reflecting a high affinity for RBCs (less than 10% plasma protein bound). The partition ratios of both drugs increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. Combination incubations showed a complex and unexplained interaction between gender and the influence of docetaxel on the partition of gemcitabine. We conclude that the incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. In combination, one anti-cancer agent can alter the partition ratios of other anti-cancer agents.

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Section: Introductionsupporting

confidence: 77%

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

Dumez

Guetens²,

Boeck³

et al. 2005

Anti-Cancer Drugs

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“…Unfortunately, the importance of sequence of gemcitabine and docetaxel has been addressed directly in only one phase I study [36]. As part of this examination of gemcitabine and docetaxel, pharmacokinetics for the D3 G and G3 D sequences were examined.…”

Section: Gemcitabine and Docetaxel: Possible Synergy?mentioning

confidence: 99%

“…As part of this examination of gemcitabine and docetaxel, pharmacokinetics for the D3 G and G3 D sequences were examined. The mean gemcitabine concentrations 30 and 90 minutes after starting a gemcitabine infusion were significantly lower after docetaxel pretreatment, but the elimination half-life was longer after such exposure, suggesting a change in drug partitioning among different blood constituents (cells, plasma proteins, plasma water) [36]. Another variable not examined in the phase I study was the fixed-dose-rate infusion schedule of gemcitabine with docetaxel.…”

Section: Gemcitabine and Docetaxel: Possible Synergy?mentioning

confidence: 99%

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Maki

2007

The Oncologist

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Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination.Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma.Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated highgrade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice.Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. The Oncologist 2007;12: 999 -1006 Disclosure of potential conflicts of interest is found at the end of this article.

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“…Published pharmacokinetic data for patients receiving gemcitabine as 800-1000 mg/m 2 over 30 min were used to design the studies. From these studies, the C max ranged from 12 to 272 lM, AUC from 14 to 95 lM h, and most of the parent molecule was nonmeasurable 1 to 2 h after the end of infusion [22][23][24][25]. For development of continuous infusions, gemcitabine given as 10 mg/m 2 /min over 2.5 h to reach a C ss of 10-20 lM were simulated [26].…”

Section: Gemcitabine Infusionsmentioning

confidence: 99%

“…It is unclear how this variability affects intracellular metabolite production and antitumor activity. We used published pharmacokinetic studies [22][23][24][25][26] to guide our initial development of this in vitro system.…”

Section: Introductionmentioning

confidence: 99%

Characterization of an in vitro cell culture bioreactor system to evaluate anti-neoplastic drug regimens

Kirstein

Brundage

Elmquist

et al. 2006

Breast Cancer Res Treat

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A dynamic 3-dimensional tissue culture system has been developed that will allow for control of gemcitabine exposure to mimic concentration-time profiles measured from biologic samples. Gemcitabine was infused into a central reservoir. Media is mixed and delivered through hollow fiber capillaries, where it diffuses into the extracapillary space containing anchorage-dependent MDA-231 cells. To test for control of gemcitabine concentration-time profiles, drug was first infused through bioreactors without cells, and gemcitabine concentrations were measured with HPLC. Concentrations could be controlled to simulate 30-min and 2.5 h infusions, and were similar in both the lumen and extracapillary space. MDA-231 cells were then seeded into control (n = 4) and gemcitabine treatment (n = 4) groups, and maintained in culture for 2 weeks. Gemcitabine (5.3 mg) was infused over 30 min to the treatment group, and blank media to the control group. Accuracy of measured gemcitabine maximum concentration (Cmax) was 83.4%, and area under the curve (AUC), 106.2%, relative to pre-experimental theoretical values. With cells present, gemcitabine AUC in the extracapillary space was 32% of the value in the lumen. For the control group, 21.2 million cells (94.3% viable) were recovered, and for the gemcitabine-treated group, 16.8 million cells (87.1 % viable). Flow cytometry showed that 13.3 % of cells in the control group were in S-phase and 34.3 % in the gemcitabine-treated group were in S-phase (p = 0.003). In conclusion, gemcitabine concentration-time profiles could be accurately controlled through dosage, infusion rate, and pump flow rate, and cells could be recovered afterward to evaluate drug treatment.

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The impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors

Cited by 23 publications

References 11 publications

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

In vitro partition of docetaxel and gemcitabine in human volunteer blood: the influence of concentration and gender

Gemcitabine and Docetaxel in Metastatic Sarcoma: Past, Present, and Future

Characterization of an in vitro cell culture bioreactor system to evaluate anti-neoplastic drug regimens

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