Marina Sáez-Belló (1), Víctor Mangas-Sanjuán (2,3), Mª Amparo Martínez-Gómez (1), Mª Ángeles López-Montenegro-Soria (4), Mónica Climente-Martí (5), Matilde Merino-Sanjuán (2,3)
(1) Foundation for the Promotion of Health and Biomedical Research of Valencia (FISABIO). Department of Pharmacy. Doctor Peset University Hospital. Valencia, Spain, (2) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia. Valencia, Spain, (3) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia. Valencia, Spain, (4) Department of Pharmacy. Lluís Alcañís Hospital. Xàtiva (Valencia), Spain, (5) Department of Pharmacy. Doctor Peset University Hospital. Valencia, Spain.
Introduction: Parenteral 5-fluorouracil (5-FU) and its oral prodrug capecitabine (CAP) are widely prescribed for treating colorectal cancer [1]. The development of grade 3-4 (G3/4) neutropenia (9 cells/L) is a common and very common adverse event in CAP monotherapy and combination schemes, respectively, with other cytostatic agents, like oxaliplatin [2]. An ideal chemotherapeutic strategy for CAP that does not result in severe neutropenia has not been established.
Objectives: to optimize the dosing strategy for capecitabine in colorectal cancer patients receiving treatment with capecitabine in monotherapy or associated with oxaliplatin based on a population pharmacokinetic / pharmacodynamic (PKPD) model.
Methods: A PKPD model able to account for the neutropenic effects after the oral administration of CAP in colorectal cancer patients with different single nucleotide polymorphisms (SNP) of the ABC gene was selected. The pharmacokinetics of CAP, 5′-deoxy-5-fluorouridine (5’-DFUR) and 5-FU were described by a concatenated three compartments model with linear absorption and disposition processes. The population pharmacokinetic (PK) model incorporates SNP rs6720173 effect on clearance of 5’-DFUR and the SNP rs2271862 effect on clearance of 5-FU [3]. The pharmacodynamic (PD) model for CAP-induced myelosuppression was based in the model previously published by Friberg et al. [4]. The final PKPD model included oxaliplatin as a significant covariate on the slope (SLP), showing a 2.84-fold increase in patients receiving oxaliplatin [5].
Stochastic simulations (n=500) were performed using different combination of statistically significant covariates. Concentration-time profiles were generated between day 7 (168 h) and day 8 (192 h) after the initiation of treatment assuming a sampling interval of 0.1 h. Absolute neutrophil count levels were simulated in the range of 0-112 days every 3 days. Exposure and safety endpoints considered were AUC5-FU between 168-192 h and neutropenia G3/4 at 4th cycle of administration, respectively. The CAP dosage ranged from 588 to 2941 mg/m2/24h (doses equivalent to 500 and 2500 mg/12h, respectively, for a patient with a body surface area of 1.7 m2) in monotherapy and in combination with oxaliplatin (130 mg/m2), for each of the selected SNPs. Dose selection was established with the goal of achieving a less than 5% probability of G3/4 neutropenia.
Results: The predicted exposure threshold that relates to the onset of G3/4 neutropenia for patients receiving CAP and oxaliplatin scheme was 26 mg·h/L, whereas 70 mg·h/L was estimated when CAP is administered as a single agent. The increased effect in patients receiving concomitant administration of oxaliplatin is manifested with a greater decrease in the level of neutrophils. Patients who are carriers of the mutated allele for SNP rs2271862 could safely receive doses of CAP in monotherapy ≤2941 mg/m2/24h (dose equivalent to 2500 mg/1.7m2/12h) and ≤1765 mg/m2/24h (dose equivalent to 1500 mg/1.7m2/12h) when the treatment with CAP is in combination with oxaliplatin (130mg/m2). Patients carrying the wild allele for SNP rs2271862 could receive doses of CAP in monotherapy ≤2353 mg/m2/24h (dose equivalent to 2000 mg/1.7m2/12h) and ≤588 mg/m2/24h (doses equivalent to 500 mg/1.7m2/12h) when CAP treatment was in combination with oxaliplatin (130 mg/m2).
Conclusions: The genetic determination of the SNP rs2271862 present in the ABC gene and the PK monitoring of 5-FU after oral administration of capecitabine or after intravenous administration of 5-FU represents a crucial information for dose individualization in patients with colorectal carcinoma. The dosing strategy proposed reduces the risk of G3/4 neutropenia, especially in patients who received concomitant treatment with oxaliplatin, which may compromise the long-term effectiveness and safety of antineoplastic treatment.
References:
[1] Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422.
[2] Sanchez-Gundin J, Torres-Suarez AI, Fernandez-Carballido AM, Barreda-Hernandez D. Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. Farm Hosp 2019; 43: 158-62.
[3] Sáez-Belló M, Mangas-Sanjuán V, López Montenegro Soria MA, Climente-Martí M, Merino-Sanjuán M. PAGE 28 (2019). Abstracts of the Annual Meeting of the Population Approach Group in Europe. ISSN 1871-6032 Abstr 8990 [www.page-meeting.org/?abstract=8990].
[4] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002 Dec 15;20(24):4713-21.
[5] Saez-Belló M. Tesis Doctoral. Personalización del tratamiento antineoplásico con capecitabina en pacientes con carcinoma colorrectal. https://hdl.handle.net/10550/72648.
Reference: PAGE () Abstr 9258 [www.page-meeting.org/?abstract=9258]
Poster: Clinical Applications