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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...

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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
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cited_by cdi_FETCH-LOGICAL-c3609-ff535c9770497ce70907896f277a8fb6d34ed2412efeb07d0defb8d5f3a70c273
cites cdi_FETCH-LOGICAL-c3609-ff535c9770497ce70907896f277a8fb6d34ed2412efeb07d0defb8d5f3a70c273
container_end_page 1337
container_issue 3
container_start_page 1327
container_title British journal of clinical pharmacology
container_volume 87
creator Royer, Bernard
Schmitt, Antonin
Nguyen, Thierry
Paillard, Marie‐Justine
Jary, Marine
Demarchi, Martin
Vernerey, Dewi
Henriques, Julie
Jacquin, Marion
Borg, Christophe
Kim, Stefano
description 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.
doi_str_mv 10.1111/bcp.14519
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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.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.14519</identifier><identifier>PMID: 32789966</identifier><language>eng</language><publisher>England</publisher><subject>body surface area ; clearance ; Cross-Over Studies ; dosing rational ; Fluorouracil ; Humans ; Liver ; population pharmacokinetics ; Quinazolines - adverse effects ; raltitrexed ; Thiophenes - toxicity</subject><ispartof>British journal of clinical pharmacology, 2021-03, Vol.87 (3), p.1327-1337</ispartof><rights>2020 The British Pharmacological Society</rights><rights>2020 The British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3609-ff535c9770497ce70907896f277a8fb6d34ed2412efeb07d0defb8d5f3a70c273</citedby><cites>FETCH-LOGICAL-c3609-ff535c9770497ce70907896f277a8fb6d34ed2412efeb07d0defb8d5f3a70c273</cites><orcidid>0000-0002-3132-7730 ; 0000-0002-1379-858X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32789966$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Royer, Bernard</creatorcontrib><creatorcontrib>Schmitt, Antonin</creatorcontrib><creatorcontrib>Nguyen, Thierry</creatorcontrib><creatorcontrib>Paillard, Marie‐Justine</creatorcontrib><creatorcontrib>Jary, Marine</creatorcontrib><creatorcontrib>Demarchi, Martin</creatorcontrib><creatorcontrib>Vernerey, Dewi</creatorcontrib><creatorcontrib>Henriques, Julie</creatorcontrib><creatorcontrib>Jacquin, Marion</creatorcontrib><creatorcontrib>Borg, Christophe</creatorcontrib><creatorcontrib>Kim, Stefano</creatorcontrib><title>Exposure‐response analysis of Raltitrexed assessing liver toxicity</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>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. 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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. 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subjects body surface area
clearance
Cross-Over Studies
dosing rational
Fluorouracil
Humans
Liver
population pharmacokinetics
Quinazolines - adverse effects
raltitrexed
Thiophenes - toxicity
title Exposure‐response analysis of Raltitrexed assessing liver toxicity
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