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4CPS-059 Case report of severe hyperbilirrubinaemia in a patient carrying polymorphisms in CES1P1, CDA, SLC22A7 and ENOSF1 treated with fluoropyrimidines
  1. Y Cura1,
  2. C Pérez-Ramírez2,
  3. A Sánchez-Martín1,
  4. MR Cantudo Cuenca1,
  5. A Jimenez-Morales1
  1. 1University Hospital Virgen de las Nieves, Pharmacogenetics Unit. Hospital Pharmacy Service, Granada, Spain
  2. 2Institute of Nutrition and Food Technology ‘José Mataix’ Center of Biomedical Research, University of Granada, Biochemistry and Molecular Biology II, Granada, Spain


Background and importance Capecitabine (Xeloda) is an oral fluoropyrimidine used for the treatment of colorectal neoplasms. Common adverse drug reactions (ADRs) during capecitabine monotherapy are gastrointestinal toxicity, hand–foot syndrome and asthenia. Haematological toxicity and hyperbilirubinaemia are also frequently reported. Currently, the genotyping of four DPYD variants is a standard practice for the prediction of capecitabine toxicity occurrence and severity. However, numerous studies have shown that other genes present in the pharmacokinetics and pharmacodynamics pathway of capecitabine may also be related with toxicity

Aim and objectives To describe a severe hyperbilirubinaemia case of a 63-year-old woman under capecitabine treatment with DPYD normal metaboliser status and genetic variants in CES1P1, CDA, SLC22A7 and ENOSF1.

Material and methods Retrospective case report. Clinical data were obtained from patient medical records. The causal relationship between capecitabine and hyperbilirubinaemia was assessed using the Naranjo algorithm. Genetic variants were analysed using real-time polymerase chain reaction (PCR) with TaqMan probes.

Results A 60-year-old woman diagnosed with stage IIIB rectal mucinous adenocarcinoma initiated neoadjuvant radiotherapy + capecitabine (1450 mg/12 hours). After cycle 1, the patient presented grade II diarrhoea and leukopenia, bilirubin of 4.50 mg/dL (VN 0.3–1.20 mg/dL), and grade I thrombocytopenia, which led to capecitabine suspension and the re-establishment of normal laboratory values. After tumour resection surgery, it was decided to initiate adjuvant capecitabine (1500 mg/12 hours) after DPYD status evaluation and with strict monitoring of bilirubin values. Genotyping analysis stated DPYD normal metaboliser profile, so treatment was initiated. 7 days later, bilirubin increased from a baseline of 0.7 to 3.5 mg/dL. Capecitabine was suspended. The patient underwent rigorous follow-up without pharmacological treatment and was diagnosed with Gilbert’s syndrome. Naranjo’s algorithm determined the ADR as probable. Exploratory genotyping was performed of >20 genes that have been previously associated with capecitabine toxicity, revealing that the patient carried CES1P1 rs7187684-CT and rs11861118-AG, CDA rs532545-TT, CDA rs602950-CC, SLC22A7 rs4149178-AA and ENOSF1 rs2612091-CT, variants that currently have a lower evidence level than DPYD and are not analysed in clinical practice.

Conclusion and relevance This case suggests that capecitabine toxicity may be influenced by other genetic variants involved in drug pharmacokinetics and pharmacodynamics beyond DPYD. However, prospective studies are required to validate these findings.

Conflict of interest No conflict of interest

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