Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Centre d'Étude et de Recours sur les Inhibiteurs de l'Angiogénèse, Paris, France.
Pascaline
P
Boudou-Rouquette
Céline
C
Narjoz
Jean Louis
JL
Golmard
Audrey
A
Thomas-Schoemann
Olivier
O
Mir
Fabrice
F
Taieb
Jean-Philippe
JP
Durand
Romain
R
Coriat
Alain
A
Dauphin
Michel
M
Vidal
Michel
M
Tod
Marie-Anne
MA
Loriot
François
F
Goldwasser
Benoit
B
Blanchet
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012867:Skin / Q000187:drug effects; D000077157:Sorafenib; D000090264:UDP-Glucuronosyltransferase 1A9
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; C000715591:UGT1A9 protein, human; D009536:Niacinamide; D000077157:Sorafenib; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9