Population pharmacokinetic and pharmacodynamic modeling of capecitabine and its metabolites in breast cancer patients

Lunar, Nastja; Étienne-Grimaldi, Marie-Christine; Macaire, Pauline; Thomas, Fabienne; Ferrero, Jean-­Marc; Pivot, Xavier; Milano, Gérard; Royer, Bernard; Schmitt, Antonin

doi:10.1007/s00280-020-04208-8

Cited by 7 publications

(9 citation statements)

References 36 publications

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“…after 15 minutes, as observed in the model of Jacobs et al 32 to gain more certainty about capecitabine absorption. The establishment of one‐compartment models for capecitabine, DFCR and DFUR was in accordance with several published population PK models 30,31,33 . Additionally, the identified flip‐flop PK of DFUR could also be observed in the model of Jacobs et al 32 …”

Section: Discussionsupporting

confidence: 84%

“…The establishment of one-compartment models for capecitabine, DFCR and DFUR was in accordance with several published population PK models. 30,31,33 Additionally, the identified flip-flop PK of DFUR could also be observed in the model of Jacobs et al 32 The population PK model structure and parameters of the regorafenib-metabolite model were similar to the published model of Keunecke et al 38 However, in our model the formation of M-5 from M-2 was established, whereas Keunecke et al assumed that M-5 is directly formed by regorafenib. 38 The proposed metabolic pathway of Gerisch et al indicated that M-5 is indeed formed by M-2 48 and our population PK model did not allow us to distinguish between both proposed pathways (Table S3.…”

Section: Discussionsupporting

confidence: 78%

“…32 One possible explanation for the identification of a dual absorption process may be the reflection of different absorption sites, namely the small intestine and the stomach. 33,46 The slow first-order absorption process as well as comparatively slower metabolite formations were presumably responsible for the occurrence of flip-flop PK for capecitabine, DFCR, and DFUR in our model. This was also indicated by biphasic declines of the concentration-time curves despite using one-compartment models.…”

Section: Discussionmentioning

confidence: 87%

“…In fact, capecitabine absorption is highly variable due to, for example, double peaks, 33 the impact of age, 31 food 46 or alterations in the gastrointestinal tract including potential gastrectomy in patients with gastro‐oesophageal cancer, for example 32 . One possible explanation for the identification of a dual absorption process may be the reflection of different absorption sites, namely the small intestine and the stomach 33,46 . The slow first‐order absorption process as well as comparatively slower metabolite formations were presumably responsible for the occurrence of flip‐flop PK for capecitabine, DFCR, and DFUR in our model.…”

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP)

Schmulenson

Bovet

Theurillat

et al. 2022

Brit J Clinical Pharma

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Aims: Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabineamplified neoadjuvant radiotherapy in LARC patients. Methods: Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact. Results: Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one and two compartment models and absorption was described by parallel firstand zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10 × 10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure. Conclusions: This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance of studying potential DDI with new anticancer drug combinations.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP)

Schmulenson

Bovet

Theurillat

et al. 2022

Brit J Clinical Pharma

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“…To be effective, capecitabine should be absorbed and converted by enzymes into deoxy-fluorocytidine (DFCR), FUDR, and 5-FU. 18 Oral absorption can be modified by intake of food or partial/total gastrectomy, and a first-pass effect plays a role in the bioavailability of capecitabine metabolites as the enzymes carboxylesterase (capecitabine / DFCR), cytidine deaminase (DFCR / FUDR), and thymidine phosphorylase (FUDR / 5-FU) are highly active in liver tissue. 19,20 Trifluridine (FTD) is a thymidine-based nucleoside analogue with antitumour activity by incorporation into DNA.…”

Section: Oral Drugs: Capecitabine and Trifluridine/tipiracilmentioning

confidence: 99%

Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature

et al. 2021

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Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.

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Current diagnostic and clinical issues of screening for dihydropyrimidine dehydrogenase deficiency

Étienne-Grimaldi

Pallet

Boige

et al. 2023

European Journal of Cancer

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Population pharmacokinetic and pharmacodynamic modeling of capecitabine and its metabolites in breast cancer patients

Cited by 7 publications

References 36 publications

Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP)

Population pharmacokinetic analyses of regorafenib and capecitabine in patients with locally advanced rectal cancer (SAKK 41/16 RECAP)

Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature

Current diagnostic and clinical issues of screening for dihydropyrimidine dehydrogenase deficiency

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