Exposure-Response Analysis of Raltitrexed Assessing Liver Toxicity
关键词
抽象
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 (DPD). 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 three weeks. However, every two weeks administration at 2 mg/m2 demonstrated a favourable toxicity profile.
Method: We performed a randomized crossover comparative population PK study between every two weeks TOMOX (RTX 2 mg/m2 ) and every three 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 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 decrease 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, CI95 = [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 that 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.
Keywords: BSA; clearance; dosing rational; population pharmacokinetics; raltitrexed.