Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

Queckenberg, Christian; Erlinghagen, V.; Baken, B. C. M.; Os, Sandra H. G. van; Wargenau, Manfred; Kubeš, V.; Peroutka, R.; Novotný, V. M. J.; Fuhr, Uwe

doi:10.1007/s00280-015-2840-6

Cited by 17 publications

(41 citation statements)

References 19 publications

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“…One tablet of 150 mg resulted in a very high plasma exposure of 5‐FU, with an AUC value around ten times higher than in pharmacokinetic studies with capecitabine in standard dosage in non‐DPD deficient patients . When correcting for the dosing interval of once every 5 days, which is ten times less than standard twice‐daily dosing, 5‐FU exposure in our patient was comparable to reference levels associated with efficacy and acceptable toxicity …”

Section: Discussionsupporting

confidence: 51%

“…One tablet of 150 mg resulted in a very high plasma exposure of 5-FU, with an AUC value around ten times higher than in pharmacokinetic studies with capecitabine in standard dosage in non-DPD deficient patients. 15,[18][19][20] When correcting for the dosing interval of once every 5 days, which is ten times less than standard twice-daily dosing, 5-FU exposure in our patient was comparable to reference levels associated with efficacy and acceptable toxicity. 15,[18][19][20] Complete DPD deficiency has not only be linked with severely increased risk for fluoropyrimidine-related toxicity, but also with neurological or developmental abnormalities in several cases.…”

Section: Discussionmentioning

confidence: 80%

“…15,[18][19][20] When correcting for the dosing interval of once every 5 days, which is ten times less than standard twice-daily dosing, 5-FU exposure in our patient was comparable to reference levels associated with efficacy and acceptable toxicity. 15,[18][19][20] Complete DPD deficiency has not only be linked with severely increased risk for fluoropyrimidine-related toxicity, but also with neurological or developmental abnormalities in several cases. [21][22][23][24][25] Our patient, however, did not present with any physical or psychomotor abnormalities.…”

Section: Discussionmentioning

confidence: 80%

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Capecitabine‐based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Henricks

Siemerink

Rosing

et al. 2017

Intl Journal of Cancer

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Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m . When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 80%

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Capecitabine‐based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Henricks

Siemerink

Rosing

et al. 2017

Intl Journal of Cancer

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“…1,2 Capecitabine can imitate the action of continuous 5-FU infusion and is an integral part of chemotherapy for the treatment of various malignancies, including colorectal cancer, gastric cancer and breast cancer. 1,2 Capecitabine can imitate the action of continuous 5-FU infusion and is an integral part of chemotherapy for the treatment of various malignancies, including colorectal cancer, gastric cancer and breast cancer.…”

mentioning

confidence: 99%

Clinical evidence of prevention strategies for capecitabine‐induced hand‐foot syndrome

Huang

Chen

et al. 2018

Intl Journal of Cancer

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Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine-containing chemotherapy. The purpose of this study was to assess the efficacies of various prevention and treatment strategies for capecitabine-induced HFS. Searches of the PubMed and Embase databases were performed to identify relevant studies. The risk ratio (RR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate the efficacies of these prevention and treatment strategies. Publication bias was evaluated using Begg's and Egger's tests. Overall and subgroup analyses were conducted. All statistical analyses were conducted with Stata software version 12.0. Seventeen eligible studies were included. Our results indicated that celecoxib was significantly associated with a lower incidence of grade ≥2 capecitabine-induced HFS without heterogeneity (RR = 0.43, 95% CI = 0.23-0.81, I = 0.0%). However, pyridoxine and topical urea/lactic acid were not effective toward preventing capecitabine-induced grade 1, 2, 3, ≥1 or ≥2 HFS. Moreover, pyridoxine was not effective in treating capecitabine-induced HFS. Similar results were obtained by subgroup analysis. Our results indicate that celecoxib has potential prophylactic efficacy for capecitabine-induced HFS. However, pyridoxine and topical urea/lactic acid are not associated with a decrease in the incidence of capecitabine-induced HFS.

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“…The identification of a healthy individual showing altered catabolism of uracil due to heterozygosity for a mutation in UPB1 suggests that also patients with a β-ureidopropionase deficiency, the third enzyme of the pyrimidine degradation pathway, might be at risk of developing 5-FU toxicity [68, 69]. Although methylenetetrahydrofolate reductase (MTHFR) is not involved in the degradation of capecitabine, a borderline decrease in the elimination-half-life of capecitabine was observed for the c.677C>T mutation in MTHFR [70]. The c.677C>T mutation in MTHFR reduces the enzyme activity and presumably increases the level of 5,10-methyleneterahydrofolate, a substrate of thymidylate synthase.…”

Section: Enzymes Of Purine and Pyrimidine Metabolismmentioning

confidence: 99%

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

2016

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Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.

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Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

Cited by 17 publications

References 19 publications

Capecitabine‐based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Capecitabine‐based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Clinical evidence of prevention strategies for capecitabine‐induced hand‐foot syndrome

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

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