1147. Genetic Polymorphisms and Its Relationship with the Concentration and Adverse Drug Reactions of Voriconazole in Taiwan
Session: Poster Abstract Session: Pharmacological Studies of Antifungals
Friday, October 9, 2015
Room: Poster Hall
Posters
  • Genetic Polymorphisms and Its Relationship with the Concentration and Adverse Drug Reactions of Voriconazole in Taiwan_v6.pdf (145.3 kB)
  • Background: Voriconazole (vori), a broad-spectrum antifungal agent, widely used as the first line treatment for invasive aspergillosis. Vori is mainly metabolized by CYP2C19, CYP2C9 and CYP3A4. The higher rate, 12.8 % to 19.8 %, of CYP2C19 poor metabolizers (PM) in Asian populations may lead to larger opportunity of concentration-dependent adverse events. This study was aimed to evaluate the association between genetic polymorphisms (SNPs), vori concentration with vori-associated adverse events (AEs).

    Methods: This prospective study was held in National Taiwan University and Koo Foundation Sun Yat-Sen Cancer Center from March 1st in 2009 to January 31st in 2011. Vori peak and trough concentration were drawn 5-7 days after the initiation of treatment. HPLC and UV light were used to detect vori concentration. The DNA samples were extracted from the patients’ white blood cell. iPLEX (Increased Plexing, Efficiency and Flexibility for MassARRAY System) was performed to detect SNPs. The Naranjo scale was applied to evaluate the causality of the AEs in relation to vori. RUCAM scale was used to further evaluate drug associated hepatotoxicity.

    Results: Among 83 patients, most of them had hematological disease (79.5 %). Thirty one patients (37.4 %) were CYP2C19 extensive metabolizers (EM), 42 patients (50.6 %) were heterozygote extensive metabolizers (HEM) and 10 patients (12.0 %) were PM. No linear relationship between CYP2C19 SNP and vori concentrations. In 49 patients on oral form of vori, HEM (3.87±2.41 mg/L) and PM patients (5.69±2.90 mg/L) had higher trough concentrations than EM patients (2.51±2.04 mg/L), with p-value 0.0494 and 0.0257, respectively. Age and CYP2C19 SNP may predict 25.7% of vori trough concentrations in these patients in the multiple regression model. The most common types of AEs were visual disturbance (42.1%), followed by hallucination (18.4%) and hepatotoxicity (39.5%) in 76 vori-associated AEs. PM patients prone to experience more vori-associated hallucination and hepatotoxicity than EM or HEM patients.

    Conclusion: The vori trough concentrations in HEM and PM patients were 1.54 and 2.3 times higher than in EM patients who took oral form of vori, respectively. PM patients tended to have higher risk of suffering vori-associated AEs; however, linear relationship was not observed between CYP2C19 SNP and vori-associated AEs.

    Yun-Ting He, M.S.1, Wei-Ting Chen, M.D.2, Yee-Chun Chen, MD, PhD3,4, Ching-Hua Kuo, Ph.D.5, Un-in Wu, M.D.4, Yu-Ting Huang, M.S.6, Yu-Ju Tseng, M.S.6, Li-Jiuan Shen, Ph.D.1,5,6 and Shu-Wen Lin, PharmD, MS1,5,6, (1)Graduate Institute of Clinical Pharmacy, National Taiwan University, Taipei, Taiwan, (2)Department of Internal Medicine, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, (3)National Taiwan University Hospital, Taipei, Taiwan, (4)Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, (5)School of Pharmacy, National Taiwan University, Taipei, Taiwan, (6)Department of Pharmacy Services, National Taiwan University Hospital, Taipei, Taiwan

    Disclosures:

    Y. T. He, None

    W. T. Chen, None

    Y. C. Chen, None

    C. H. Kuo, None

    U. I. Wu, None

    Y. T. Huang, None

    Y. J. Tseng, None

    L. J. Shen, None

    S. W. Lin, None

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