Pharmacokinetics of Gemcitabine at Fixed-Dose Rate Infusion in Patients with Normal and Impaired Hepatic Function

Felici, Alessandra; Segni, Susanna Di; Milella, Michèle; Colantonio, Simona; Sperduti, Isabella; Nuvoli, B.; Contestabile, M.; Sacconi, Andrea; Zaratti, Massimo; Citro, Gennaro; Cognetti, Francesco

doi:10.2165/00003088-200948020-00005

Cited by 12 publications

(11 citation statements)

References 21 publications

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“…A small phase II study in 43 patients with advanced unresectable hepatobiliary carcinomas revealed a high frequency (30%) of grade 3/4 thrombocytopenias in the 18 patients with hepatocellular carcinoma and liver cirrhosis (Child A: n = 5, Child B: n = 13) of this group [59]. In contrast, a smaller study involving 9 patients with pancreatic (n = 5) or biliary tract cancer (n = 4) and hepatic impairment showed that the full dose of gemcitabine can be safely used in patients with elevated total bilirubin and transaminases when administered via the slower 10-mg/m 2 /min infusion [60]. Another recent study in 12 patients with advanced pancreatic (n = 7) or biliary tract cancer (n = 5) and extra- or intrahepatic cholestasis, receiving gemcitabine plus capecitabine chemotherapy, revealed a further interesting aspect: A total bilirubin level of ≥ 2 × ULN was associated with an impaired intracellular activation of gemcitabine to gemcitabine triphosphates, suggesting limited anti-tumour activity [61].…”

Section: Resultsmentioning

confidence: 99%

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

Vogel

Kullmann

Kunzmann³

et al. 2015

Oncol Res Treat

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In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab-paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab-paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis.

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Section: Resultsmentioning

confidence: 99%

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

Vogel

Kullmann

Kunzmann³

et al. 2015

Oncol Res Treat

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“…This makes the use of sample stabilizer necessary. Even with a stabilizer, many clinical studies in the literature report placing samples on ice and/or immediate centrifugation and freezing before measuring [13, 14, 17, 19, 39, 44]. This is not so practical in routine clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Rapid Homogeneous Immunoassay to Quantify Gemcitabine in Plasma for Therapeutic Drug Monitoring

Kozo

Ross

Jarrah

et al. 2017

Therapeutic Drug Monitoring

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Background Gemcitabine (2′,2′-difluoro-2′-deoxycytidine) is a nucleoside analog used as a single agent and in combination regimens for the treatment of a variety of solid tumors. Several studies have shown a relationship between gemcitabine peak plasma concentration (Cmax) and hematological toxicity. An immunoassay for gemcitabine in plasma was developed and validated to facilitate Therapeutic Drug Monitoring (TDM) by providing an economical, robust method for automated chemistry analyzers. Methods A monoclonal antibody was coated on nanoparticles to develop a homogenous, agglutination inhibition assay. To prevent ex vivo degradation of gemcitabine in blood, tetrahydrouridine (THU) was used as a sample stabilizer. Validation was conducted for precision, recovery, cross-reactivity, and linearity on a Beckman Coulter AU480. Verification was done on an AU5800 in a hospital laboratory. A method comparison was performed with LC-MS/MS utilizing clinical samples. Selectivity was demonstrated by testing cross-reactivity of the major metabolite, 2′,2′-difluorodeoxyuridine (dFdU). Results Coefficients of variation for repeatability and within-laboratory precision were <8%. Measured values deviated <3% from assigned. Linear range was from 0.40 to 33.02 μg/mL (1.5–125.5 μM). Correlation with validated LC-MS/MS methods was R2 = 0.977. The assay was specific for gemcitabine: there was no cross-reactivity to dFdU, chemotherapeutics, concomitant or common medications tested. THU was packaged in single-use syringes. Gemcitabine stability in whole blood was extended to 8 hours (RT) and in plasma to eight days (2–8 °C). Conclusions The assay demonstrated the selectivity, test range, precision, and linearity to perform reliable measurements of gemcitabine in plasma. The addition of stabilizer improved the sample handling. Using general clinical chemistry analyzers, gemcitabine could be measured for TDM.

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“…The drug is excreted primarily by the kidneys, and it therefore has to be used with caution in patients with renal dysfunction. Gemcitabine can also cause transient transaminitis, but no dose adjustment is typically required with fixed dosing 82,83 .…”

Section: Gemcitabinementioning

confidence: 99%

Systemic Treatment Approaches in her2-Negative Advanced Breast Cancer—Guidance on the Guidelines

et al. 2015

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Despite advancements in the treatment of early-stage breast cancer, many patients still develop disease recurrence; others present with de novo metastatic disease. For most patients with advanced breast cancer, the primary treatment intent is noncurative—that is, palliative—in nature. The goals of treatment should therefore focus on maximizing symptom control and extending survival. Treatments should be evaluated on an individualized basis in terms of evidence, but also with full respect for the wishes of the patient in terms of acceptable toxicity. Given the availability of extensive reviews on the roles of endocrine therapy and her2 (human epidermal growth factor receptor 2)–targeted therapies for advanced disease, we focus here mainly on treatment guidelines for the non-endocrine management of her2-negative advanced breast cancer in a Canadian health care context.

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Pharmacokinetics of Gemcitabine at Fixed-Dose Rate Infusion in Patients with Normal and Impaired Hepatic Function

Cited by 12 publications

References 21 publications

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine

Rapid Homogeneous Immunoassay to Quantify Gemcitabine in Plasma for Therapeutic Drug Monitoring

Systemic Treatment Approaches in her2-Negative Advanced Breast Cancer—Guidance on the Guidelines

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