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

Serdjebi, Cindy; Gattacceca, Florence; Seitz, Jean‐François; Fein, Francine; Gagnière, Johan; François, Ετιεννε; Abakar-Mahamat, Abakar; Deplanque, Gaël; Rachid, Madani; Lacarelle, Bruno; Ciccolini, Joseph; Dahan, Laétitia

doi:10.1097/ftd.0000000000000399

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…Interestingly, we also observed a trend toward lower response rates in patients with elevated CDA activity. Although not statistically significant, this relationship is in line with our previous work demonstrating the link between CDA UM status and treatment failure with gemcitabine in pancreatic cancer 35 and with azacytidine in patients with chronic myelomonocytic leukemia. 22 Similarly, we also observed a trend toward longer PFS and OS in patients with CDA below the 2 U/mg threshold, thus illustrating how toxicity and efficacy are intricately linked with Ara-C in this setting.…”

Section: Discussionsupporting

confidence: 76%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

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Key Points• Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common.• We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine.Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 713 (Ara-C 1 anthracyclines)protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 6 0.7 U/mg vs 3.95 6 3.1 U/mg; Student t test P , .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 6 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

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Section: Discussionsupporting

confidence: 76%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

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“…Therefore, an unknown mechanism other than CDA-mediated 5'-DFCR metabolism might exist to explain our findings. A similar phenomenon was reported for gemcitabine, where the metabolic activity converting gemcitabine to an inactive metabolite dFdU catalyzed by CDA increased as the renal function decreased (10), hence a common mechanism may exist.…”

Section: Discussionsupporting

confidence: 70%

Correlation Between the Metabolic Conversion of a Capecitabine Metabolite, 5’-Deoxy-5-fluorocytidine, and Creatinine Clearance

Inaishi

Fujita

Matsumoto

et al. 2020

In Vivo

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Aim: Capecitabine is a prodrug that is metabolized to its active form, , in three enzymatic steps. This prospective pharmacokinetic study evaluated cytidine deaminase (CDA) activity, the second drugmetabolizing enzyme that generates 5'-deoxy-5-fluorouridine (5'-DFUR) from 5'-deoxy-5-fluorocytidine (5'-DFCR), as well as creatinine clearance (CLcr). Patients and Methods: Patients with colorectal cancer who received capecitabine plus oxaliplatin were selected. Pharmacokinetics of capecitabine and its metabolites, and CDA activity in plasma were analyzed. Results: Eighteen patients were examined. The area under the plasma concentration-time curve (AUC) of 5'-DFUR showed a significant inverse correlation with CLcr (p=0.003). The metabolic ratio, i.e. the ratios of the AUC of 5'-DFUR plus that of 5-FU to the AUC of 5'-DFCR, significantly increased when CLcr decreased (p=0.001) but did not depend on plasma CDA activity. Conclusion: Metabolism of 5'-DFCR to form 5'-DFUR increased as CLcr decreased but the mechanism remains unknown.Capecitabine is an oral fluoropyrimidine that is designed to be finally metabolized to an active metabolite, 5-fluorouracil (5-FU). After oral administration, capecitabine is rapidly absorbed through the intestine and is metabolized to 5'deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase in the liver. Subsequently, 5'-DFCR is converted to 5'-deoxy-5fluorouridine (5'-DFUR) by cytidine deaminase (CDA) in the liver and tumor tissues. It is finally converted to 5-FU by thymidine phosphorylase, which is predominantly expressed in tumor tissues (1, 2).A previous pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC) of 5'-DFUR (AUC 5'-DFUR ) in patients with renal impairment was significantly higher than that in patients with normal renal function, resulting in a higher incidence of capecitabine-induced adverse events in patients with renal impairment (3). Therefore, reduction of the starting dose of capecitabine is recommended according to measures of the patient's renal function, such as creatinine clearance (CLcr) (3). It is believed that increased systemic exposure to 5'-DFUR in patients with impaired renal function is likely to be caused by delayed renal excretion of the metabolite. However, according to the pharmacokinetic parameters of capecitabine and its metabolites, the maximum concentration (C max ) of 5'-DFUR was higher in patients with renal impairment than that in patients with normal renal function but the elimination half-life (t 1/2 ) was similar in both patient groups (3), suggesting that 5'-DFUR might accumulate due to the increased production of 5'-DFUR rather than by its delayed renal excretion. Therefore, we hypothesized that systemic exposure to 5'-DFUR is associated with the metabolic activity of CDA, which primarily generates 5'-DFUR from 5'-DFCR, rather than the delayed renal excretion of 5'-DFUR.This study carefully evaluated the effects of CDA activity, as well as CLcr, on systemic exposure to 5'-DFCR 3539 This article is freely ...

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“…PK-PD analyses have been attempted for decitabine dosage adjustment but still need some refinements [179]. For gemcitabine, although target concentrations are seemingly not available yet, sparse sampling methods provide reliable model-based PK predictions which may simplify the future application of TDM for this drug [180]. Occurrence of acute kidney injury correlates with high clofarabine AUC, prompting the need for further investigations to define the toxicity threshold [181].…”

Section: Clinical Application Of Lc-ms/ms Results For the Tdm Of Cyto...mentioning

confidence: 99%

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update

Briki,

Murisier,

Guidi

et al. 2024

Journal of Chromatography B

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

Cited by 4 publications

References 25 publications

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

Correlation Between the Metabolic Conversion of a Capecitabine Metabolite, 5’-Deoxy-5-fluorocytidine, and Creatinine Clearance

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update

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