Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.

BACKGROUND: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. METHODS: Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. RESULTS: A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. CONCLUSIONS: Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.

Incidence of inflammatory bowel disease in Corsica from 2002 to 2003.

OBJECTIVES: The aim of this prospective epidemiological study was to determine the incidence of inflammatory bowel diseases (IBD) in Corsica using the same methodology as that of the EPIMAD registry. METHODS: Between January 1st, 2002 and December 31, 2003, all gastroenterologists in Corsica (N=19) enrolled patients consulting for the first time with clinical symptoms compatible with IBD. Each case was reviewed by another expert gastroenterologist to assign a diagnosis of definite, probable, possible Crohn's disease (CD), ulcerative colitis (UC) or unclassified/able chronic colitis. RESULT: Eighty-one new cases were recorded, including seventy-one diagnoses of IBD (definite and probable cases), with 20 (28%) CD, 49 (69%) UC and 2 (3%) unclassifiable chronic colitis. The age-adjusted incidence (per 105 inhabitants/year) was 4.05 for CD and 9.5 for UC. The female/male ratio and median age at time of diagnosis were 1.3 and 29 years for CD and 0.63 and 44 years for UC, respectively. The median time from symptom onset to diagnosis was five months for both diseases. CONCLUSION: In Corsica, the observed incidence of CD is close to that observed in other metropolitan French regions. These data are contrary to the north-south gradient reported for this disease. Our figure of 9.5/10(5) for UC in Corsica is two-fold higher than reported in other metropolitan French regions. Genetic and/or environmental factors may explain these findings.

[Cancer of an ectopic pancreas in the duodenal wall]. / Cancer sur pancréas ectopique de la paroi duodénale.

Ectopic pancreas is defined as pancreatic tissue outside the normal location of the pancreas. It can be affected by the same complications as the orthotopic pancreas, such as adenocarcinoma. This extremely rare complication (only 14 published cases) may have a better prognosis that adenocarcinoma of an orthotopic pancreas. Endoscopic ultrasonography may be useful in the diagnosis of this disease. We report a case of malignancy of the duodenal wall originating in aberrant pancreatic tissue, and review the literature.

FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.

PURPOSE: Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. EXPERIMENTAL DESIGN: One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. RESULTS: Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients. CONCLUSION: This study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT01416662.

Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia.

The acute phase of Crohn's disease (CD) is characterized by a large afflux of polymorphonuclear leukocytes (PMNL) into the mucosa and by the release of TNF-alpha. Conversion of inactive TNF-alpha into an active form requires the cleavage of a transmembrane TNF-alpha precursor by the TNF-alpha-converting enzyme (ADAM17), a protease mainly regulated by the tissue inhibitor of metalloproteinase 3 (TIMP3). The aim of the present study was to investigate in an in vitro model of PMNL transepithelial migration and in the intestinal mucosa of patients with CD the expression and regulation of ADAM17 and TIMP3 in intestinal epithelial cells (IEC). ADAM17 and TIMP3 expression was analyzed by Western blotting, RT-PCR, confocal microscopy, and immunohistochemistry by using the T84 model and digestive biopsies. ADAM17 expression in IEC was increased at a posttranscriptional level during the early phase (from 2 to 4 h) of PMNL transepithelial migration whereas TIMP3 was only increased 24 h later. TNF-alpha induced an early upregulation of ADAM17 in T84 cells, whereas PMNL adhesion, H(2)O(2), or epithelial tight junction opening alone did not affect the amount of ADAM17. Immunohistochemistry of intestinal biopsies revealed that strong expression of ADAM17 was associated with a high activity of CD. In contrast, TIMP3 was very poorly expressed in these biopsies. ADAM17 and TIMP3 profiling did not correlated with the NOD2/CARD15 status. The ADAM17 activity was higher both in the early phase of PMNL transepithelial migration and in active CD. These results showed early posttranscriptional upregulation of ADAM17 in IEC linked to PMNL transepithelial migration and a high activity of CD.