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02.01.2021 | Original Article

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

verfasst von: Nastja Lunar, Marie-Christine Etienne-Grimaldi, Pauline Macaire, Fabienne Thomas, Florence Dalenc, Jean-Marc Ferrero, Xavier Pivot, Gérard Milano, Bernard Royer, Antonin Schmitt

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2021

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Abstract

Purpose

The present study was performed to examine relationships between systemic exposure of capecitabine metabolites (5-FU, 5′-DFCR and 5′-DFUR) and toxicity or clinical response in patients with metastatic breast cancer.

Methods

A population pharmacokinetic model for capecitabine and its three metabolites was built. Typical parameter values, characteristics of random distributions, associated with parameters, and covariates impact were estimated. Area under the curve (AUC) were computed for 5-FU and compared with grades of toxicity. Pharmacokinetic modeling was based on data collected on the first treatment cycle. Toxicity was assessed on the two first treatment cycles.

Results

The study was conducted in 43 patients. The population pharmacokinetic model (a one-compartment model per compound) was able to capture the very complex absorption process of capecitabine. Statistically significant covariates were cytidine deaminase, alkaline phosphatase and dihydrouracilemia (UH₂)/uracilemia (U) ratio. UH₂/U ratio was the most significant covariate on 5-FU elimination and CDA on the transformation of 5′-DFCR in 5′-DFUR. A trend was observed between 5-FU AUC and thrombopenia toxicity grades, but not with other toxicities. Best clinical response was not linked to systemic exposure of capecitabine metabolites.

Conclusion

In our study, we propose a model able to describe, meanwhile, and its main metabolites, with a complex absorption process and inclusion of enzyme activity covariates such as CDA and UH₂/U ratio.

Trial registration Eudract 2008-004136-20, 2008/11/26

Nur mit Berechtigung zugänglich

Nishijima TF, Suzuki M, Muss HB (2016) A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 156:227–236. https://doi.org/10.1007/s10549-016-3756-5CrossRefPubMedPubMedCentral

Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281. https://doi.org/10.1016/s0959-8049(98)00058-6CrossRefPubMed

Gieschke R, Burger H-U, Reigner B, Blesch KS, Steimer J-L (2003) Population pharmacokinetics and concentration–effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol 55:252–263CrossRef

Urien S, Rezaí K, Lokiec F (2005) Pharmacokinetic modelling of 5-FU production from capecitabine—a population study in 40 adult patients with metastatic cancer. J Pharmacokinet Pharmacodyn 32:817–833. https://doi.org/10.1007/s10928-005-0018-2CrossRefPubMed

Reigner B, Verweij J, Dirix L, Cassidy J, Twelves C, Allman D, Weidekamm E, Roos B, Banken L, Utoh M, Osterwalder B (1998) Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res 4:941–948PubMed

Jacobs BAW, Deenen MJ, Joerger M, Rosing H, de Vries N, Meulendijks D, Cats A, Beijnen JH, Schellens JHM, Huitema ADR (2019) Pharmacokinetics of capecitabine and four metabolites in a heterogeneous population of cancer patients: a comprehensive analysis. CPT Pharmacomet Syst Pharmacol. 8:940–50. https://doi.org/10.1002/psp4.12474CrossRef

Lemaitre F, Goirand F, Launay M, Chatelut E, Boyer J-C, Evrard A, Paludetto M-N, Guilhaumou R, Ciccolini J, Schmitt A (2018) Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer. Bull Cancer 105:790–803. https://doi.org/10.1016/j.bulcan.2018.06.008CrossRefPubMed

Daher Abdi Z, Lavau-Denes S, Prémaud A, Urien S, Sauvage FL, Martin J, Leobon S, Marquet P, Tubiana-Mathieu N, Rousseau A (2014) Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer. Cancer Chemother Pharmacol 73:1285–1293. https://doi.org/10.1007/s00280-014-2466-0CrossRefPubMedPubMedCentral

Francois E, Bennouna J, Chamorey E, Etienne-Grimaldi MC, Renée N, Senellart H, Michel C, Follana P, Mari V, Douillard JY, Milano G (2012) Phase I trial of gemcitabine combined with capecitabine and erlotinib in advanced pancreatic cancer: a clinical and pharmacological study. Chemotherapy 58:371–380. https://doi.org/10.1159/000343969CrossRefPubMed

10.

Etienne-Grimaldi M-C, Boyer J-C, Beroud C, Mbatchi L, van Kuilenburg A, Bobin-Dubigeon C, Thomas F, Chatelut E, Merlin J-L, Pinguet F, Ferrand C, Meijer J, Evrard A et al (2017) New advances in DPYD genotype and risk of severe toxicity under capecitabine. PLoS One. https://doi.org/10.1371/journal.pone.0175998CrossRefPubMedPubMedCentral

11.

Peters GJ, Honeywell RJ, Maulandi M, Giovannetti E, Losekoot N, Etienne-Grimaldi M-C, Milano G, Serdjebi C, Ciccolini J, EORTC-Pharmacology and Molecular Mechanism Group (2014) Selection of the best blood compartment to measure cytidine deaminase activity to stratify for optimal gemcitabine or cytarabine treatment. Nucleosides Nucleotides Nucleic Acids. 33:403–12. https://doi.org/10.1080/15257770.2014.894196CrossRefPubMed

12.

Reigner B, Clive S, Cassidy J, Jodrell D, Schulz R, Goggin T, Banken L, Roos B, Utoh M, Mulligan T, Weidekamm E (1999) Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients. Cancer Chemother Pharmacol 43:309–315. https://doi.org/10.1007/s002800050900CrossRefPubMed

13.

Christophidis N, Mihaly G, Vajda F, Louis W (1979) Comparison of liquid- and gas-liquid chromatographic assays of 5-fluorouracil in plasma. Clin Chem 25:83–86CrossRef

14.

Montange D, Bérard M, Demarchi M, Muret P, Piédoux S, Kantelip JP, Royer B (2010) An APCI LC-MS/MS method for routine determination of capecitabine and its metabolites in human plasma. J Mass Spectrom 45:670–677. https://doi.org/10.1002/jms.1759CrossRefPubMed

15.

Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11:371–380. https://doi.org/10.1208/s12248-009-9112-5CrossRefPubMedPubMedCentral

16.

Gieschke R, Steimer J-L, Reigner BG (1998) Relationships between metrics of exposure to Xeloda and occurence of adverse effects. In: Annual meeting of the American Society of Clinical Oncology

17.

Kaldate RR, Haregewoin A, Grier CE, Hamilton SA, McLeod HL (2012) Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6. Oncologist 17:296–302. https://doi.org/10.1634/theoncologist.2011-0357CrossRefPubMedPubMedCentral

18.

Capitain O, Asevoaia A, Boisdron-Celle M, Poirier A-L, Morel A, Gamelin E (2012) Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II. Proof-of-Concept Study Clinical Colorectal Cancer 11:263–267. https://doi.org/10.1016/j.clcc.2012.05.004CrossRefPubMed

19.

Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, Dorval E, Piot G, Morel A, Boisdron-Celle M (2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 26:2099–2105. https://doi.org/10.1200/JCO.2007.13.3934CrossRefPubMed

20.

Fety R, Rolland F, Barberi-Heyob M, Hardouin A, Campion L, Conroy T, Merlin JL, Rivière A, Perrocheau G, Etienne MC, Milano G (1998) Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res 4:2039–2045PubMed

21.

Thyss A, Milano G, Renée N, Vallicioni J, Schneider M, Demard F (1986) Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer. Cancer Chemother Pharmacol 16:64–66CrossRef

22.

Patel JN, O’Neil BH, Deal AM, Ibrahim JG, Sherrill GB, Olajide OA, Atluri PM, Inzerillo JJ, Chay CH, McLeod HL, Walko CM (2014) A Community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy. Oncologist 19:959–965. https://doi.org/10.1634/theoncologist.2014-0132CrossRefPubMedPubMedCentral

23.

Davies NM, Takemoto JK, Brocks DR, Yáñez JA (2010) Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet 49:351–377. https://doi.org/10.2165/11319320-000000000-00000CrossRefPubMed

24.

Byon W, Fletcher CV, Brundage RC (2008) Impact of censoring data below an arbitrary quantification limit on structural model misspecification. J Pharmacokinet Pharmacodyn 35:101–116. https://doi.org/10.1007/s10928-007-9078-9CrossRefPubMed

25.

Jusko WJ (2012) Use of pharmacokinetic data below lower limit of quantitation values. Pharm Res 29:2628–2631. https://doi.org/10.1007/s11095-012-0805-6CrossRefPubMedPubMedCentral

26.

Keizer RJ, Jansen RS, Rosing H, Thijssen B, Beijnen JH, Schellens JHM, Huitema ADR (2015) Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses. Pharmacol Res Perspect. https://doi.org/10.1002/prp2.131CrossRefPubMedPubMedCentral

27.

Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, Astier A, Chatelut E (2014) Review of therapeutic drug monitoring of anticancer drugs part 1–cytotoxics. Eur J Cancer 50:2010–2019. https://doi.org/10.1016/j.ejca.2014.04.014CrossRefPubMed

28.

Rudek MA, Connolly RM, Hoskins JM, Garrett-Mayer E, Jeter SC, Armstrong DK, Fetting JH, Stearns V, Wright LA, Zhao M, Watkins SP, McLeod HL, Davidson NE et al (2013) Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer. Breast Cancer Res Treat 139:135–143. https://doi.org/10.1007/s10549-013-2516-zCrossRefPubMedPubMedCentral

29.

Paule I, Tod M, Hénin E, You B, Freyer G, Girard P (2012) Dose adaptation of capecitabine based on individual prediction of limiting toxicity grade: evaluation by clinical trial simulation. Cancer Chemother Pharmacol 69:447–455. https://doi.org/10.1007/s00280-011-1714-9CrossRefPubMed

30.

Liu D, Li X, Li X, Zhang M, Zhang J, Hou D, Tong Z, Dong M (2019) CDA and MTHFR polymorphisms are associated with clinical outcomes in gastroenteric cancer patients treated with capecitabine-based chemotherapy. Cancer Chemother Pharmacol 83:939–949. https://doi.org/10.1007/s00280-019-03809-2CrossRefPubMed

31.

García-González X, Cortejoso L, García MI, García-Alfonso P, Robles L, Grávalos C, González-Haba E, Marta P, Sanjurjo M, López-Fernández LA (2015) Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget 6:6422–6430CrossRef

32.

Caronia D, Martin M, Sastre J, de la Torre J, García-Sáenz JA, Alonso MR, Moreno LT, Pita G, Díaz-Rubio E, Benítez J, González-Neira A (2011) A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res 17:2006–2013. https://doi.org/10.1158/1078-0432.CCR-10-1741CrossRefPubMed

33.

Gamelin E, Boisdron-Celle M, Guérin-Meyer V, Delva R, Lortholary A, Genevieve F, Larra F, Ifrah N, Robert J (1999) Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 17:1105. https://doi.org/10.1200/JCO.1999.17.4.1105CrossRefPubMed

34.

Boisdron-Celle M, Remaud G, Traore S, Poirier AL, Gamelin L, Morel A, Gamelin E (2007) 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Lett 249:271–282. https://doi.org/10.1016/j.canlet.2006.09.006CrossRefPubMed

35.

Meulendijks D, Henricks LM, Jacobs BAW, Aliev A, Deenen MJ, de Vries N, Rosing H, van Werkhoven E, de Boer A, Beijnen JH, Mandigers CMPW, Soesan M, Cats A et al (2017) Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Br J Cancer 116:1415–1424. https://doi.org/10.1038/bjc.2017.94CrossRefPubMedPubMedCentral

36.

Chu MP, Hecht JR, Slamon D, Wainberg ZA, Bang Y-J, Hoff PM, Sobrero A, Qin S, Afenjar K, Houe V, King K, Koski S, Mulder K et al (2017) Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol 3:767–773. https://doi.org/10.1001/jamaoncol.2016.3358CrossRefPubMed

37.

Sáez-Belló M, Mangas-Sanjuán V, Martínez-Gómez MA, Soria MÁL-M, Climente-Martí M, Merino-Sanjuán M (2020) Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations. Br J Clin Pharmacol. https://doi.org/10.1111/bcp.14441CrossRefPubMed

38.

Goirand F, Lemaitre F, Launay M, Tron C, Chatelut E, Boyer J-C, Bardou M, Schmitt A (2018) How can we best monitor 5-FU administration to maximize benefit to risk ratio? Expert Opin Drug Metab Toxicol 14:1303–1313. https://doi.org/10.1080/17425255.2018.1550484CrossRefPubMed

39.

Morawska K, Goirand F, Marceau L, Devaux M, Cueff A, Bertaut A, Vincent J, Bengrine-Lefevre L, Ghiringhelli F, Schmitt A (2018) 5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer. Oncotarget 9:11559–11571. https://doi.org/10.18632/oncotarget.24338CrossRefPubMedPubMedCentral

Titel: Population pharmacokinetic and pharmacodynamic modeling of capecitabine and its metabolites in breast cancer patients
verfasst von: Nastja Lunar
Marie-Christine Etienne-Grimaldi
Pauline Macaire
Fabienne Thomas
Florence Dalenc
Jean-Marc Ferrero
Xavier Pivot
Gérard Milano
Bernard Royer
Antonin Schmitt
Publikationsdatum: 02.01.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2021
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04208-8

Springer Medizin

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