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Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort

Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort. Dr. Yu-Li Liu National Health Research Institutes April 18, 2013. Acknowledgement. NHRI Dr. Ho, IK ( 何英剛 ), Dr. Lin, KM ( 林克明 ), Dr. Wang, SC ( 王聲昌 )

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Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort

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  1. Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort Dr. Yu-Li Liu National Health Research Institutes April 18, 2013

  2. Acknowledgement • NHRI • Dr. Ho, IK (何英剛), Dr. Lin, KM (林克明), Dr. Wang, SC (王聲昌) • Dr. Tsou, HH (鄒小蕙), Dr. Hsiao, CF (蕭金福), Dr. Lin, PS (林培生), Dr. Tsai, HJ (蔡慧如), Dr. Chung, RH (鍾仁華) • Research Assistants Kuo, HW (郭湘維), Liu, SC (劉淑芝), Fang, CP (方秋萍), Chang, YS (張耀升), Liu, SW (劉聖文), Chen, CY (陳俊宇), Chen, YT (陳昱廷), Lin, YC (林義傑) • Research Nurses Tsui-Mei Hung (洪翠妹), Yu-Ching Lin (林玉琴), Miao-Fang Lee (李妙芳), Ming-Chu Tseng (鄭明珠), Yu-Hun Tsai (蔡玉涵), and Shu-Chuan Ting (丁淑娟) • Collaboration hospitals and psychiatrists • Happy Kuy-Lok Tan (陳快樂),Li-Nen Lin (林立寧), Lien-Wen Su (束連文), Chieh-Liang Huang (黃介良), Yih-Hong Yang (楊逸鴻), Chen, CH (陳佳惠) • No conflict of interests

  3. Pharmacogenomics • A new field of study belongs to the branch of pharmacology • Correlating single-nucleotide polymorphisms (SNPs) or gene expression with a drug's efficacy or toxicity. • Pharmacogenetics examine the single gene interactions with drugs. • Pharmacogenomics is the whole genome application of pharmacogenetics.

  4. Requires in Pharmacogenomics Study • Patient Compliance • Research nurse observation • Therapeutic drug monitoring (steady-state plasma concentration) • Well Designed Clinical Trial • Institutional Review Boards (IRBs) • Patient demographics (age, gender, body weight..) • Define inclusion and exclusion criteria • Patient co-medication record • Treatment efficacy (or responses) • Adverse reactions • Register at NIH with a trial number

  5. Methadone Maintenance Treatment (MMT) in Taiwan • First Started at 2006 • More than 90 hospitals provided patients methadone • 11,000 heroin dependent patients under MMT • Purposes: reducing heroin abuse, reducing spread of infectious diseases, ex. HIV, HCV, and reducing crime rate • Large inter-patient variation • Methadone dosing strategy ranging from 5 mg/d to 180 mg/d • Lethal complication (cardiac arrest, respiratory depression etc.) • Inter-individual variability on drug metabolism • Drug-drug interaction: other illicit substances, alcohol, anti-HIV drugs

  6. Study design • Cross-sectional design • Plasma methadone and metabolite concentrations were measured • Genes were selected and genotyped for single nucleotide polymorphisms (SNPs) • Literature report • Han Chinese tagSNPs from HapMap • Functional SNPs • Clinical response information were recorded and cleaned up by the Clinical Trial Information Management System (CTIMeS)

  7. Taipei City Hospital-Songde Branch 臺北市立聯合醫院 松德院區 Taipei City Hospital-Yangming Branch 臺北市立聯合醫院 陽明院區 Far Eastern Memorial Hospital 亞東紀念醫院 Taoyuan Mental Hospital 桃園療養院 En Chu Kong Hospital 恩主公醫院 Wei-Gong Memorial Hospital 為恭紀念醫院醫院 China Medical University Hospital 中國醫藥大學附設醫院 Sample size: 366

  8. Subjects Inclusion criteria: • Chinese ethnicity. • Men or women above age of 18. • Able to participate in a clinical assessment in Chinese (including Mandarin and Taiwanese dialects). • Individuals who were willing to provide blood and urine samples for analyses. • Heroin dependence rated by DSM-IV definition. • Enter methadone maintenance therapy for at least 3 months. • Methadone dosage change < 10 mg in the past 1 week. • Individuals who have completed a written consent form.

  9. Subjects Exclusion criteria: • Patients with comorbid severe mental disorders including 1) Organic mental disorders, 2) Schizophrenia • Patients who were pregnant. • Severe cognitive impairment.

  10. Assessments • Outcome measurement • Urine drug screening (morphine/amphetamine) • Clinical interview: TOP (Treatment Outcomes Profile) • Self-report of illicit drug use and SDS (severity of drug dependence) • Drug effect assessment • Opioid withdrawal symptom/sign: Clinical opioid withdrawal scale (COWS); 11 items • Opioid intoxication sign: pupil size, respiratory rate, heart rate • Adverse effects: Treatment emergent symptoms scale (TESS); 31 items • Plasma drug concentration monitoring • Methadone enantiomeres: R-methadone, S-methadone • EDDP enantiomers: R-EDDP, S-EDDP • DNA genotyping • CYP3A4, CYP2B6, CYP2C19, UGT2B7, opioid receptors

  11. General Demography

  12. Withdrawal Symptoms

  13. Methadone Induced Side Effects

  14. Other Substance Use

  15. Pharmacokinetics • Absorption • Distribution • Metabolism • Excretion Genes SNP or Gene Dose or Matrix Co-medications Treatment Responses Other Substances Dose Infectious status Side Effects Plasma Concentration Withdrawals

  16. Methadone Metabolism CYP2B6 (S) CYP2C19 (R) CYP3A4 Development of a method to measure methadone enantiomers and its metabolites without enantiomer standard compounds for the plasma of methadone maintenance patients. Biomed. Chromatogr. 2010, 24(7): 782-788.

  17. CYP2B6 • Summary • SNP markers in CYP2B6 are associated with plasma S-methadone concentration, ratio of S-methadone/dose, and S-methadone clearance. CYP2B6 Polymorphisms Influence the Plasma Concentration and Clearance of the Methadone S-Enantiomer. J. Clin. Psychopharmacol. 2011, 31(4): 463-469.

  18. HCV Infection Status (Poster C8)

  19. CYP3A4 • Summary • Three SNPs located at CYP3A4 intron region showed significant association with withdrawal symptom score, side effect symptom score, and betel nut use. • The higher the withdrawal symptoms scores, the higher the side effect symptom score, but lower the betel nut use. Genetic polymorphisms of CYP3A4 indicate the withdrawal symptoms, adverse reactions and betel nut use in methadone maintenance patients. Pharmacogenomics 2011, 12(10): 1397-1406.

  20. CYP2C19 • Summary • Gene dose in CYP2C19 is associated with methadone dose, and ratios of R-methadone/dose, and R-EDDP/dose. • Gene dose is associated with TESS scores in urine morphine test positive patients. The extensive metabolizer had higher side effect score than poor metabolizer.

  21. CYP2C19 x CYP2B6 Interaction

  22. CYP2C19 x CYP3A4 Interaction

  23. CYP2C19 x CYP2B6 x CYP3A4

  24. Tolerance (Poster C14)

  25. Morphine Metabolism

  26. UGT2B7 UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients. Pharmacogenomics 2012, 13(8):879-888.

  27. Pharmacodynamics • Drug action • Receptor interaction • Receptor-coupled Response Genes SNP or Gene Dose or Matrix Co-medications Treatment Responses Other Substances Dose Infectious status Side Effects Plasma Concentration Withdrawals

  28. OPRM1 Opioid receptor Mu1 genetic polymorphisms are associated with adverse reactions in methadone maintenance Patients. Eur. Neuropsychopharmacol. 2012, 22(10): 695-703.

  29. OPRM1 and Smoking OPRM1 genetic polymorphisms are associated with the plasma nicotine metabolite cotinine concentration in methadone maintenance patients: a cross sectional study. J. Hum. Gen. 2013, 58: 84-90.

  30. Pharmacokinetics • (Physical Dependence) • Absorption • Distribution • Metabolism • Excretion • Pharmacodynamics • (Psychological Dependence) • Drug action • Receptor interaction • Receptor-coupled Response Genes Genes SNP or Gene Dose or Matrix SNP or Gene Dose or Matrix Co-medications Treatment Responses Other Substances Dose Infectious status Side Effects Plasma Concentration Withdrawals

  31. Limitations • 81% male • 95% HCV positive • 50% Patients urine morphine test positive • Sample size is small • More studies in replicating these results are essential for future treatment guidelines.

  32. In Summary • Methadone dosage regiment is combined the influence of pharmacokinetic and pharmacodynamic genetic variants. • The pharmacokinetic genes of SNPs may predict the plasma methadone concentration, methadone dosage and withdrawal severities. • The pharmacodynamic genes of SNPs may influence the dosage prediction and the treatment side effects. • Pharmacogenomics study promises the advent of personalized medicine. • More methods warrant further investigation to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. • Methadone pharmacogenomics study may provide a key to decipher the mechanism for opioid dependence.

  33. Acknowledgement • Funding • A pharmacogenomic study on methadone therapeutics (NSC98-3112-B-400-011-, NSC99-3112-B-400-003-, NSC100-3112-B-400-015-, from May, 2009- April, 2012) • Pharmacogenomics study of opioid receptor and UGT2B7 genes in methadone treatment (NSC 100-2314-B-400-002-MY3, from Aug 2011 – Jul, 2014) • Liver cytochrome P-450 isozyme alterations after prenatal opiates exposure and extend clinical study (PH-098-PP-36; PH-099, 100-PP-37; PH-101-32, from 2009 - 2012) • Technical Supports • Clinical Trial Information Management System (CTIMeS) • National Center for Genome Medicine (NCGM) at Academia Sinica, Taiwan, for genotyping/technical support

  34. Thanks for Attention

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