Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.
<h4>Background</h4>Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The...
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2012
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oai:doaj.org-article:80507bd316a74a50b6e32edbe689dc732021-11-18T07:08:57ZEarly sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.1932-620310.1371/journal.pone.0042875https://doaj.org/article/80507bd316a74a50b6e32edbe689dc732012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22912756/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors.<h4>Methods</h4>Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis.<h4>Results</h4>Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUC(cum)) was independently associated with any grade ≥ 3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥ 2 diarrhea (p = 0.015) and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUC(cum) value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018).<h4>Conclusion</h4>In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.Pascaline Boudou-RouquetteCéline NarjozJean Louis GolmardAudrey Thomas-SchoemannOlivier MirFabrice TaiebJean-Philippe DurandRomain CoriatAlain DauphinMichel VidalMichel TodMarie-Anne LoriotFrançois GoldwasserBenoit BlanchetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42875 (2012) |
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Medicine R Science Q Pascaline Boudou-Rouquette Céline Narjoz Jean Louis Golmard Audrey Thomas-Schoemann Olivier Mir Fabrice Taieb Jean-Philippe Durand Romain Coriat Alain Dauphin Michel Vidal Michel Tod Marie-Anne Loriot François Goldwasser Benoit Blanchet Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| description |
<h4>Background</h4>Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors.<h4>Methods</h4>Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis.<h4>Results</h4>Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUC(cum)) was independently associated with any grade ≥ 3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥ 2 diarrhea (p = 0.015) and female gender with grade ≥ 2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUC(cum) value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥ 3 toxicity (p = 0.018).<h4>Conclusion</h4>In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results. |
| format |
article |
| author |
Pascaline Boudou-Rouquette Céline Narjoz Jean Louis Golmard Audrey Thomas-Schoemann Olivier Mir Fabrice Taieb Jean-Philippe Durand Romain Coriat Alain Dauphin Michel Vidal Michel Tod Marie-Anne Loriot François Goldwasser Benoit Blanchet |
| author_facet |
Pascaline Boudou-Rouquette Céline Narjoz Jean Louis Golmard Audrey Thomas-Schoemann Olivier Mir Fabrice Taieb Jean-Philippe Durand Romain Coriat Alain Dauphin Michel Vidal Michel Tod Marie-Anne Loriot François Goldwasser Benoit Blanchet |
| author_sort |
Pascaline Boudou-Rouquette |
| title |
Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| title_short |
Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| title_full |
Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| title_fullStr |
Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| title_full_unstemmed |
Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| title_sort |
early sorafenib-induced toxicity is associated with drug exposure and ugtia9 genetic polymorphism in patients with solid tumors: a preliminary study. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/80507bd316a74a50b6e32edbe689dc73 |
| work_keys_str_mv |
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| _version_ |
1718423861210382336 |