Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′‐difluorodeoxyuridine and their nucleotides

Derissen, Ellen J. B.; Huitema, Alwin D. R.; Rosing, Hilde; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1111/bcp.13557

Cited by 30 publications

(29 citation statements)

References 40 publications

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“…However, it is possible to observe that the PBPK model tends to overestimate the population variability of dFdC AUC. PBPK dFdCTP tumor AUC results slightly lower with respect to dFdCTP WBC AUC simulated with the Zhang model, but it shows good agreement with the results presented in Derissen et al 43 As a further simulation exercise, 3.34 mmol/m 2 of dFdC were infused weekly for 20 weeks; results are shown in the Supplementary Materials, Section S5.2. From these results, it is possible to see that there is no accumulation of dFdC and dFdCTP, in agreement with De Lange et al 45 Global sensitivity analysis A variance-based GSA on the PBPK model coupled with the metabolic network was performed with the aim of understanding what the most important parameters are in explaining plasma dFdC and tumor dFdCTP concentration AUC variability in the population.…”

Section: Multiscale Pk Model For Dfdc In Pancreatic Cancersupporting

confidence: 83%

“…In Table 3, the metrics simulated with the PBPK model for plasma dFdC and tumor dFdCTP concentrations are compared with those simulated with the Zhang model and with in vivo patients PK data from the literature. 43,44 For the two in vivo studies, metrics related to the tumor dFdCTP concentration were not available, thus, the ones relative to WBC dFdCTP concentration are reported. Concerning the dFdC plasma AUC and peak plasma concentration (C max ), the results of the PBPK model show good agreement with both the Zhang model and the literature data.…”

Section: Multiscale Pk Model For Dfdc In Pancreatic Cancermentioning

confidence: 99%

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Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Garcia‐Cremades

Melillo

Trocóniz

et al. 2020

Clinical Translational Sci

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The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2', 2'-difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of this kind of modeling strategy. A mechanistic model characterizing dFdC metabolic pathway (metabolic network) was developed using in vitro literature data from two pancreatic cancer cell lines. The network was able to describe the time course of extracellular and intracellular dFdC metabolites concentrations. Moreover, a physiologically-based pharmacokinetic model was developed to describe clinical dFdC profiles by using enzymatic and physiological information available in the literature. This model was then coupled with the metabolic network to describe the dFdC active metabolite profile in the pancreatic tumor tissue. Finally, global sensitivity analysis was performed to identify the parameters that mainly drive the interindividual variability for the area under the curve (AUC) of dFdC in plasma and of its active metabolite (dFdCTP) in tumor tissue. From this analysis, cytidine deaminase (CDA) concentration was identified as the main driver of plasma dFdC AUC interindividual variability, whereas CDA and deoxycytidine kinase concentration mainly explained the tumor dFdCTP AUC variability. However, the lack of in vitro and in vivo information needed to characterize key model parameters hampers the development of this kind of mechanistic approach. Further studies to better characterize pancreatic cell lines and patient enzymes polymorphisms are encouraged to refine and validate the current model. 2′,2′-difluorodeoxycytidine (gemcitabine, dFdC) is a nucleoside antimetabolite prodrug effective against several solid tumors. 1-4 Treatment with dFdC represents the firstline therapy of pancreatic cancer, that constitutes one of the most aggressive and lethal oncology diseases, with an overall 5-year survival rate of < 5%. 5 As a prodrug, dFdC has to be intracellularly metabolized to its active metabolite, dFdC triphosphate (dFdCTP), to Multiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al. www.cts-journal.comMultiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al. www.cts-journal.comMultiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al.

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Section: Multiscale Pk Model For Dfdc In Pancreatic Cancersupporting

confidence: 83%

Section: Multiscale Pk Model For Dfdc In Pancreatic Cancermentioning

confidence: 99%

Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Garcia‐Cremades

Melillo

Trocóniz

et al. 2020

Clinical Translational Sci

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“…[35][36][37][38] Furthermore, gemcitabine is considered a promising agent for combination therapy in the clinical setting. 39 It is a deoxycytidine analog in which the two hydrogen atoms at the 2′-position of the deoxyribose moiety are replaced by fluorine, 40 which could functionally inhibit DNA methyltransferase and DNA biosynthesis. 41,42 Previously, only gemcitabine was used as first-line therapy for mCRPC, but the PSA response rate and disease control rate of this strategy are not high.…”

Section: Discussionmentioning

confidence: 99%

Docetaxel‐resistant prostate cancer cells become sensitive to gemcitabine due to the upregulation of ABCB1

et al. 2020

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Background Docetaxel is the preferred chemotherapeutic agent for hormone‐refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. Objective We aimed to establish docetaxel resistance in castration‐resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC‐3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. Methods Human PC cells (DU145, PC‐3, CWR22) and all docetaxel‐resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel‐resistant CRPCs prepared for flow cytometry. For the evaluation of tumor‐suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. Results The P‐glycoprotein‐encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel‐resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel‐resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel‐sensitive and docetaxel‐resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. Conclusion This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

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“…In this case, one compartment does not suffice to describe the concentration‐time profile of distribution and multiple compartments may be required to adequately describe the profile. On a more advanced level, the intracellular distribution can be taken into account . Distribution in children is affected by altering body composition, for example, changes in water/fat ratio, muscle ratio, and extracellular water .…”

Section: Admementioning

confidence: 99%

“…On a more advanced level, the intracellular distribution can be taken into account. 41,42 Distribution in children is affected by altering body composition, for example, changes in water/fat ratio, muscle ratio, and extracellular water. 32,43,44 Plasma protein concentration and binding can differ as well, which is important for highly protein-bound drugs.…”

Section: Distributionmentioning

confidence: 99%

Pharmacokinetics and population pharmacokinetics in pediatric oncology

Sassen

Zwaan

Sluis

et al. 2019

Pediatric Blood & Cancer

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Pharmacokinetic research has become increasingly important in pediatric oncology as it can have direct clinical implications and is a crucial component in individualized medicine. Population pharmacokinetics has become a popular method especially in children, due to the potential for sparse sampling, flexible sampling times, computing of heterogeneous data, and identification of variability sources. However, population pharmacokinetic reports can be complex and difficult to interpret. The aim of this article is to provide a basic explanation of population pharmacokinetics, using clinical examples from the field of pediatric oncology, to facilitate the translation of pharmacokinetic research into the daily clinic.

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Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′‐difluorodeoxyuridine and their nucleotides

Abstract: The study provides the first complete picture of all nucleotides that are formed intracellularly during gemcitabine treatment. Low intracellular dFdU nucleotide concentrations were found, which calls into question the relevance of these nucleotides for the cytotoxic effects of gemcitabine.

Cited by 30 publications

References 40 publications

Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Docetaxel‐resistant prostate cancer cells become sensitive to gemcitabine due to the upregulation of ABCB1

Pharmacokinetics and population pharmacokinetics in pediatric oncology

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