Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort
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Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort
Dr. Yu-Li LiuNational 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 )
– 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
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.
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
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
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)
China Medical University Hospital中國醫藥大學附設醫院
Wei-Gong Memorial Hospital為恭紀念醫院醫院
Taipei City Hospital-Yangming Branch臺北市立聯合醫院 陽明院區
En Chu Kong Hospital恩主公醫院
Taoyuan Mental Hospital桃園療養院
Taipei City Hospital-Songde Branch臺北市立聯合醫院 松德院區Far Eastern Memorial Hospital亞東紀念醫院
Sample size: 366
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.
Subjects
Exclusion criteria: • Patients with comorbid severe mental
disorders including 1) Organic mental disorders,
2) Schizophrenia• Patients who were pregnant. • Severe cognitive impairment.
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
General Demography Overall Urine Morphine Positive Urine Morphine Negative
P-valueN=366 n=185 n=178
Mean ± SD Mean ± SD Mean ± SD
Age (years) 38.17 ± 7.72 38.37 ± 7.96 37.87 ± 7.46 0.57a
Male 297 (81.2%) 152 (82.2%) 142 (79.8%) 0.56b
BMI (kg/m-1) 23.58 ± 3.52 23.62 ± 3.57 23.59 ± 3.49 0.89a
Starting dose of Methadone (mg/day) 32.04 ± 11.15 31.64 ± 10.07 32.44 ± 12.22 0.77a
Current dose of Methadone (mg/day) 54.67 ± 28.12 54.53 ± 26.07 55.32 ± 30.13 0.88a
R-Methadone/methadone dose ratio 3.86 ± 2.32 3.7 ± 2.71 4.03 ± 1.82 0.001a
S-Methadone/methadone dose ratio 2.77 ± 1.57 2.58 ± 1.45 2.98 ± 1.66 0.012a
R-EDDP/methadone dose ratio 0.31 ± 0.5 0.26 ± 0.33 0.33 ± 0.54 0.26a
S-EDDP/methadone dose ratio 0.33 ± 0.49 0.31 ± 0.38 0.33 ± 0.58 0.95a
Human immunodeficiency virus (HIV) 86 (24.0%) 50 (27.3%) 36 (20.8%) 0.15b
Hepatitis C virus (HCV) 334 (94.9%) 173 (96.1%) 158 (93.5%) 0.27b
Values are shown as mean ± SD or N (%). Bold P-value: P<0.05. a Wilcoxon rank-sum test. b Chi-Square test.
Withdrawal Symptoms Overall Urine Morphine Positive Urine Morphine Negative
P-valuea P-valueb,cN=366 N=185 N=178
n % Mean ± SD n % Mean ± SD n % Mean ± SD
Sum of COWS 366 1.49 ± 1.86 185 1.51 ± 1.93 178 1.44 ± 1.78 0.85
Heart Rate 365 77.55 ± 11.86 184 76.83 ± 11.29 178 78.20 ± 12.24 0.37
Pupil size 69 18.9% 0.21 ± 0.46 34 18.5% 0.20 ± 0.44 35 19.7% 0.22 ± 0.48 0.74 0.77b
Sweating 41 11.2% 0.13 ± 0.40 26 14.1% 0.17 ± 0.48 14 7.9% 0.08 ± 0.30 0.06 0.06b
Tremor 39 10.7% 0.15 ± 0.46 20 10.8% 0.13 ± 0.40 19 10.7% 0.17 ± 0.53 0.91 0.97b
Anxiety or Irritability 39 10.7% 0.12 ± 0.35 19 10.3% 0.12 ± 0.37 19 10.7% 0.11 ± 0.31 0.94 0.90b
Bone or Joint aches 36 9.8% 0.11 ± 0.36 24 13.0% 0.14 ± 0.38 11 6.2% 0.08 ± 0.33 0.033 0.028b
Runny nose or tearing 31 8.5% 0.11 ± 0.39 14 7.6% 0.10 ± 0.36 17 9.6% 0.13 ± 0.43 0.49 0.50b
Restlessness 24 6.6% 0.07 ± 0.25 15 8.1% 0.08 ± 0.27 8 4.5% 0.04 ± 0.21 0.16 0.16b
GI Upset 16 4.4% 0.07 ± 0.33 9 4.9% 0.08 ± 0.39 7 3.9% 0.05 ± 0.27 0.65 0.67b
Yawning 10 2.7% 0.04 ± 0.23 6 3.2% 0.04 ± 0.25 3 1.7% 0.02 ± 0.18 0.34 0.50c
Gooseflesh skin 8 2.2% 0.07 ± 0.44 4 2.2% 0.06 ± 0.44 4 2.3% 0.07 ± 0.45 0.96 1.00c
Values are shown as mean ± SD or n, %. Bold P-value: P<0.05. a Wilcoxon rank-sum test. b Chi-Square test. c Fisher Exact test.
Methadone Induced Side Effects Overall Urine Morphine Positive Urine Morphine Negative
P-valuea P-valuebN=366 N=185 N=178
n % Mean ± SD n % Mean ± SD n % Mean ± SD
Constipation 248 67.8% 1.96 ± 0.84 125 67.6% 2.01 ± 0.85 121 68.0% 1.92 ± 0.83 0.40 0.93
Sedation 172 47.0% 1.51 ± 0.70 94 50.8% 1.51 ± 0.68 77 43.3% 1.49 ± 0.72 0.73 0.15
Change in Libido 111 30.3% 1.72 ± 0.79 63 34.1% 1.70 ± 0.75 47 26.4% 1.77 ± 0.84 0.76 0.11
Dry Mouth 101 27.6% 1.55 ± 0.70 59 31.9% 1.61 ± 0.74 41 23.0% 1.49 ± 0.64 0.49 0.06
Impaired Mentation 79 21.6% 1.61 ± 0.72 41 22.2% 1.78 ± 0.76 37 20.8% 1.43 ± 0.65 0.032 0.75
Excessive Sweating 71 19.4% 1.86 ± 0.85 38 20.5% 1.95 ± 0.87 32 18.0% 1.75 ± 0.84 0.34 0.54
Insomnia 67 18.3% 1.93 ± 0.78 32 17.3% 2.03 ± 0.78 34 19.1% 1.85 ± 0.78 0.36 0.66
Fatigue 65 17.8% 1.62 ± 0.78 32 17.3% 1.78 ± 0.79 32 18.0% 1.47 ± 0.76 0.08 0.87
Difficulty with Urination 52 14.2% 1.38 ± 0.60 28 15.1% 1.50 ± 0.69 23 12.9% 1.26 ± 0.45 0.24 0.54
Increase in Appetite 46 12.6% 1.48 ± 0.59 25 13.5% 1.52 ± 0.51 21 11.8% 1.43 ± 0.68 0.37 0.62
Decrease in Appetite 44 12.0% 1.55 ± 0.70 26 14.1% 1.50 ± 0.71 18 10.1% 1.61 ± 0.70 0.54 0.25
Weight Gain 38 10.4% 1.68 ± 0.74 18 9.7% 1.67 ± 0.59 20 11.2% 1.70 ± 0.86 0.86 0.64
Weakness 33 9.0% 1.36 ± 0.70 18 9.7% 1.56 ± 0.86 14 7.9% 1.14 ± 0.36 0.17 0.53
Malaise 27 7.4% 1.48 ± 0.64 13 7.0% 1.62 ± 0.65 13 7.3% 1.38 ± 0.65 0.31 0.92
Tachycardia/Palpitations 25 6.8% 1.44 ± 0.71 14 7.6% 1.43 ± 0.65 10 5.6% 1.50 ± 0.85 1.00 0.45
Values are shown as mean ± SD or n, %. Bold P-value: P<0.05. a Wilcoxon rank-sum test. b Chi-Square test.
Other Substance Use Total
N=366 Urine Morphine PositiveN=185 Urine Morphine Negative
N=178P-valuea
n % n % n %
Opiates 234 63.9% 171 92.4% 61 34.3% <0.0001
Alcohol 116 31.7% 56 30.3% 59 33.1% 0.56
Betel nut 95 26.0% 42 22.7% 52 29.2% 0.16
Amphetamine 64 17.5% 38 20.5% 25 14.0% 0.10
Cocaine 0 0.0% 0 0.0% 0 0.0%
Cannabis 0 0.0% 0 0.0% 0 0.0% Values are shown as n, %. Bold P-value: P<0.05.
a Chi-Square test.
Pharmacokinetics
Absorption Distribution Metabolism Excretion
Genes
SNP or Gene Dose or Matrix
Dose
Plasma Concentration
Co-medicationsTreatment ResponsesOther Substances
Infectious status Side Effects
Withdrawals
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.
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.
HCV Infection Status (Poster C8)
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.
CYP2C19Summary•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.
CYP2C19 x CYP2B6 Interaction
CYP2C19 x CYP3A4 Interaction
CYP2C19 x CYP2B6 x CYP3A4
Tolerance (Poster C14)
Morphine Metabolism
UGT2B7
UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients. Pharmacogenomics 2012, 13(8):879-888.
Genes
SNP or Gene Dose or Matrix
Dose
Plasma Concentration
Co-medicationsTreatment ResponsesOther Substances
Pharmacodynamics
Drug action Receptor interaction Receptor-coupled Response
Infectious status Side Effects
Withdrawals
OPRM1
Opioid receptor Mu1 genetic polymorphisms are associated with adverse reactions in methadone maintenance Patients. Eur. Neuropsychopharmacol. 2012, 22(10): 695-703.
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.
Pharmacokinetics(Physical Dependence)
Absorption Distribution Metabolism Excretion
Genes Genes
SNP or Gene Dose or Matrix
SNP or Gene Dose or Matrix
Dose
Plasma Concentration
Co-medicationsTreatment ResponsesOther Substances
Pharmacodynamics(Psychological Dependence) Drug action Receptor interaction Receptor-coupled Response
Infectious status Side Effects
Withdrawals
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.
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.
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
Thanks for Attention