Exposure‐response analysis of Raltitrexed assessing liver toxicity

Aim Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5‐fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to...

Full description

Saved in:
Bibliographic Details
Published in:British journal of clinical pharmacology 2021-03, Vol.87 (3), p.1327-1337
Main Authors: Royer, Bernard, Schmitt, Antonin, Nguyen, Thierry, Paillard, Marie‐Justine, Jary, Marine, Demarchi, Martin, Vernerey, Dewi, Henriques, Julie, Jacquin, Marion, Borg, Christophe, Kim, Stefano
Format: Article
Language:English
Subjects:
body surface area
clearance
Cross-Over Studies
dosing rational
Fluorouracil
Humans
Liver
population pharmacokinetics
Quinazolines - adverse effects
raltitrexed
Thiophenes - toxicity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Aim Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5‐fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m2 every 3 weeks. However, every 2 weeks administration at 2 mg/m2 demonstrated a favourable toxicity profile. Method We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m2) and every 3 weeks TOMOX (RTX 3 mg/m2). Results A three‐compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48‐10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates‐based dose was calculated, leading to less variability in AUC than observed with the actual BSA‐based or fixed doses. Conclusion These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
ISSN:0306-5251
1365-2125
DOI:10.1111/bcp.14519