Pharmacogenomics of DMEs PGEN I

Introduction and

CYP3A, TPMT, ALDH2, UGT, GSTM1, HLA

MEDCH 527

Optimization of Drug Therapy

•  Individualized drug therapy is an old concept, based on the recognition that individual patients can have markedly different responses to a standardized treatment regimen.

Efficacy: Estimated that 20-75% of subjects in recent major clinical trials 14 drug categories) derived no clinical benefit from treatment.

Toxicity: Estimated that serious ADRs (requiring hospitalization) occurred

at an incidence rate of 6.7% (1966-96), and there were ~100,000 fatal ADRs/year (JAMA 279:1200-5, 1998).

1 Treat with alternative drug or dose

Profile for non-response

or toxicity

Treat with conventional drug or dose

Profile for favorable response

2

Promise of PM/PGX Testing

Population stratification into sub-groups with

similar phenotypes.

Drug Sponsor Indication Gene/Genotype(s) Effect of Genotype

Abacavir GSK HIV-1 HLA-B *5701 Hypersensitivity

Azathioprine Prometheus Renal allograft transplantation, RA, IBD

TPMT *2, TPMT*3A, TPMT *3C

Chronic myelotoxicity and resulting in neutropenia

Carbamazepine Novartis Epilepsy HLA-B *1502

Stevens-Johnson syndrome and Toxic epidermal necrolysis

Cetuximab Imclone Metastatic colo- rectal cancer

KRAS mutations in codons 12/13

Loss of efficacy

Clopidogrel BMS Anticoagulation CYP2C19*2 CYP2C19*3

Loss of efficacy

Irinotecan Pfizer Metastatic colo- rectal cancer

UGT1A1*28 Severe diarrhea, neutropenia

Panitumamab Amgen Metastatic colo- rectal cancer

KRAS mutations in codons 12/13

Loss of efficacy

Trastuzumab Genentech HER2+ breast cancer

HER2 expression HER2 expression needed for therapeutic benefit

Warfarin BMS Anticoagulation

VKORC1 variants, CYP2C9*3

Bleeding complications

Genetic Information on Drug Labels – adapted from Hudson KL. NEJM 365, 2011.

CCT – Pro CTT - Leu

•  ~3 billion bases in the genome; DNA variation occurs on widely different scales:

- Deletions, Insertions, Rearrangements

- Copy number variation (CNVs) e.g. XAAGAAGX àXAAGAAGAAGAAGX

- Epigenetic variation - e.g. DNA methylation

- Single nucleotide polymorphisms (SNPs) e.g. 1079C à1079T

coding variation (synonymous and non-synonymous) non-coding variation (intronic, flanking)

•  SNPs are frequent, occurring about once in every 1000 DNA bases when comparing 2 individuals (varies considerably with region); over 50 M identified (dbSNP)

Major Types of Genetic Variation

Gene Structure and Expression

I II III

Introns

II III ImRNA Protein

Splicing

I II III

Promoter

Primary RNA

DNA

Transcription

(Mature)

Exons

Translation

O-Me

Post-Translational Modification

3’ 5’

Regulation of Translation By microRNA

3’-UTR 5’-UTR

Regulation of Transcription by NRs

Enhancer Epigenetic

Loci

Allele: Any site(s) of sequence variation in a gene e.g. C430>T in CYP2C9 --> CYP2C9*2

Polymorphism: Occurs when the commonest identifiable allele has a

frequency no greater than 0.99 - ‘Polymorphic variant’: Frequency ≥ 0.01 - ‘Common variant’ Frequency ≥ 0.10 - ‘Rare variant’: Frequency < 0.01

SNP: Single Nucleotide Polymorphism Haplotype: Patterns of co-occurrence of variant sites within a gene Pharmacogenetics: Study of the effect of genetic variability on the toxicity of

drugs and other xenobiotics: - focus on monogenic traits and drug disposition

Pharmacogenomics: Application of genomic information to understanding

individual variations in drug response: - focus on polygenic traits and disease states

Monogenic Pharmacogenetic Disorders - Historical and P450 Based

Disorder Gene Pivotal reference Phenylthiourea non-taster TAS2R1 Snyder, 1932; Atypical serum cholinesterase BCHE Kalow and Genest, 1957 Glucose-6-phosphate dehydrogenase deficiency G6PD Marks and Gross, 1959 Isoniazid slow N-acetylation NAT2 Evans et al., 1960 Fish-odor syndrome; Trimethylaminuria FMO3 Humbert et al., 1970 Debrisoquine/sparteine poor metabolizer CYP2D6 Eichelbaum, 1975 S-mephenytoin oxidation deficiency CYP2C19 Kupfer and Preisig, 1984 Coumarin, Nicotine oxidase deficiency CYP2A6 Yamano et al., 1989 Warfarin (Tolbutamide) oxidation defect CYP2C9 Steward et al., 1997 Tacrolimus oxidation deficiency CYP3A5 Keuhl et al., 2001

Adapted/condensed from Nebert and Vessell, Eur. J. Pharmacol. (2004)

Polygenic Nature of Drug Effects

Host Susceptibility Genes

Disease Pathogenesis Genes

Drug Receptor/Target Genes

Drug Disposition Genes

Efficacy

Toxicity

William Evans, SJCRH

Top 200 in US - 2008

Covered here

Mechanisms of Genetic Variation Among P450s

Adapted from M. Ingelman-Sundberg, Mutat. Res. (2001)

Single Gene Duplicated Gene

RNA xs mRNA

No Altered Low enzyme Normal High enzyme enzyme enzyme level enzyme expression expression

1) protein instability 2) altered Km, Vmax 3) substrate specificity

No Metabolism Reduced Metabolism Normal Metabolism Increased Metabolism CYP2D6*5 CYP2D6*10, CYP2C9*11 CYP2D6*1XN CYP2A6*4 CYP2C9*3, CYP2D6*17 CYP2A6*1X2 CYP2D6*4 CYP2C19*2

Continuum of phenotypic effects?

Deleted Gene

no mRNA Coding SNP

Reg. SNP

The Concept of Extensive Metabolizer and Poor Metabolizer Phenotypes and Effects on Drug Clearance

frequ

ency

1 10 100

• early stop codon • unstable protein • exon skipping • no transcript • gene deletion

• promoter SNPs • amino acid substitutions • regulatory SNPs

frequ

ency

1 10 100 “PM” “EM”

Drug Clearance Adapted from W. Evans, St. Jude

CYP3A4 Polymorphisms • ~22 unique alleles (many coding-region SNPs) identified for CYP3A4 gene – see the P450 allele web-site (www.cypalleles.ki.se/cyp3a4.htm)

• At least one of these (3A4*20 - a frameshift inducing a truncated protein) abolishes enzyme activity in vitro, but the allele frequency activity is extremely low (<0.06% in a white German population). CYP3A4*22 associated with low mRNA levels (allelic imbalance) and reduced simvastatin clearance (Elens et al, Pharmacogenet Genomics, 2011)

Ingelman-Sundberg et al., The Pharmacogenomics Journal (2013)

Kuehl et al., 2001; Lin et al., 2002

1 2 3 4 5 6 7 8 9 10 11 12 13 3B

CYP3A5*3 (G) CYP3A5*1 (A)

CYP3A5 protein

1 2 3 4 5 6 7 8 9 10 11 12 13 5’ UTR 3’ UTR

(wt-CYP3A5 mRNA) (SV1-CYP3A5 mRNA)

A→G (intron-3)

truncated, inactive protein

1 2 3 4 5 6 7 8 9 10 11 12 13

CYP3A5 Genetic Polymorphism

Representative CYP3A5 Substrates Anti-cancer Drugs vincristine (neurotoxicity) irinotecan (efficacy response rate) etoposide (efficacy)

Immunosuppressants cyclosporine (neurotoxicity, renal toxicity) tacrolimus (neurotoxicity, renal toxicity)

Antimalarials quinine (cinchonism)

Sedative/Hypnotics alprazolam midazolam

Metabolic Fate of Tacrolimus

Tacrolimus

13-DMT 12-HT 31-DMT

12-OH-DMT

CYP3A5>4

CYP3A5>4

CYP3A5>4

•  Tacrolimus is used to prevent grafted organ rejection (immune suppressant) •  CYP3A5 is one of 2 enzymes (also CYP3A4) that metabolically clear tacrolimus

from the body •  CYP3A5 makes all 4 primary metabolites, but preferentially the major one (13-

DMT), 12-HT and, 31-DMT

15-DMT CYP3A4>5

Contribution of CYP3A5 to Hepatic Tacrolimus Metabolism

13-DMT Formation

CYP3A4 Km (µM) Vmax (nmol/min/nmol) Clint (ml/min/nmol)

0.21 8.0 38

CYP3A5 Km (µM) Vmax (nmol/min/nmol) Clint (ml/min/nmol)

0.21 17.0 82

Human Liver Microsomes

Tacrolimus Disappearance (mL/min/mg)

CYP3A4

6.1

(3.6)

CYP3A4 +CYP3A5

15.9 (9.8)

Unbound 13-DMT formation clearance (rCYP3A) and unbound liver microsomal tacrolimus disappearance clearance

Dai et al., DMD, 2006

The CYP3A4 content for the 10 matched microsomal preparations represented in each group was equivalent. The nominal initial tacrolimus conc was 0.2 µM; unbound conc determined after measurement of nonspecific binding.

Unbound Km and Clint calculated after correction for nonspecific binding.

CYP3A5 Genotype and In Vivo Tacrolimus Disposition

Haufroid et al. 2004

High CLint

Low CLint

Tacrolimus Metabolic Clearance In Vivo

•  Subjects carrying a functional CYP3A5*1 allele have a higher clearance than those with two variant alleles.

•  The importance of individual metabolic pathways and sensitivity to the CYP3A5 genotype matches the in vitro prediction. Zheng et al, CPT, 2012

CYP3A5*1 and Tacrolimus Clinical Outcomes

Ojo, NEJM, 2003

Table 4. Mean apparent urinary tacrolimus clearance based on a 96-hour collection

Mean tac CLurinary

based on AUCblood

Mean tac CLurinary/eGFR based on AUCblood

Mean tac CLurinary based on AUCplasma

Mean tac CLurinary/eGFR based on AUCplasma CYP3A5 expressors 2.01±0.57 0.017±0.007 50.15±13.67 0.41±0.17

CYP3A5 nonexpressors 3.15±1.69 0.029±0.019 97.71±59.89 0.89±0.66 Difference% -36.2% -41.7%

-48.7%

-53.9%

P value 0.04 0.05 0.01 0.02

Zheng et al, Clin Pharmacol Ther, 2012

O

O OCH3

O O

H

H

O

OHGua-N7

AFB1 Guanine-N7 adduct

O

O OCH3

O O

H

H

O

OHGS

AFB1 GSH adduct

O

O

O

OCH3

O O

H

H

O

O OCH3

O O

H

H

O

O

O

O OCH3

O O

H

H

O

HOOH

AFB1 AFB1 exo-8,9-epoxide AFB1 dihydrodiol

CYP3A

GSH GST

DNA

H2O

EH

multiple monohydroxylation and keto reduction products

CYP3A5*1 allele associated with higher

aflatoxin-albumin adducts in Africans

(Wojnowski et al, 2004)

Aflatoxin Activation -

CYP3A5

Protein-S-aflatoxin adduct (e.g., albumin adduct)

Non-toxic

Primary elimination pathway

Non-toxic

Toxic DNA Adduct Non-toxic: BIOMARKER FOR EXPOSURE TO AFB

Non-CYP, Polymorphic Phase I Enzymes

FMO TMA, nicotine, cimetidine

xanthine oxidase theophylline

cholinesterase succinylcholine

paroxonase organophosphates

ADH ethanol

ALDH2 acetaldehyde

ALDH2 Polymorphisms

•  ALDH2*2: Glu487Lys substitution at the NAD+ binding domain causes a 150x increase in the Km for cofactor binding (probably affecting on/off of NAD+ and NADH) and 10x decrease in Vmax. Intrinsic clearance profoundly reduced.

•  High frequency in Asian populations

E + NAD+ E-NAD+ + S S-E-NAD+ P-E-NADH P-E + NADH E + P

NAD+ Binding NADH Release Product Release Substrate Binding Hydride Transfer

(steps for forward reaction described)

•  ALDH2 catalyzes the elimination of acetaldehyde from the body (converts it to acetic acid).

•  Individuals homozygous and heterozygous for the ALDH2*2 allele have a pronounced impairment in their ability to clear acetaldehyde after ingestion of an acetaldehyde source (e.g., ethanol); 220x and 47x increase in the AUC, respectively.

•  Acetaldehyde accumulation results in profound cardiovascular changes; e.g., increase in arterial blood flow to the face (flushing).

Acetaldehyde – ALDH2 Genotypes

ALDH2*2/*2

ALDH2*1/*1

ALDH2*1/*2

•  M=methoxyacetaldehyde; A = Acetaldehyde; B = benzaldehyde; P = propionaldehyde •  Because ALDH2 is functional as a tetramer and heteroteramers exhibit reduced function, the *2 allele

appears semi-dominant. Strongly associated with reduced risk of alcoholism (presumably an aversion to acetaldehyde). Other data suggests increased risk of MALD (ME) toxicity in *2 carriers (Ginsberg et al., Reg Toxicol Pharmacol 36:297-309, 2002).

TPMT: thiopurine methyltransferase XO: xanthine oxidase HGPRT: hypoxanthine guanine phosphoribosyltransferase TIMP: 6-thioinosine monophosphate MTMP: 6-S-methylthioinosine monophosphate TGN: 6-thioguanine nucleotides 6-MP: 6-mercaptopurine MeMP: 6-S-methylmercaptopurine 6-TU: 6-thiouric acid

6-MP TGN

MeMP

TPMT

6-TU

XO

HGPRT DNA

TPMT

Bioactivation Pathway

Det

oxifi

catio

n Pa

thwa

y

TIMP

MTMP

N

N

N

NH

SH

TPMT

(multiple enzymatic steps)

(Purine salvage)

TPMT and 6-Mercaptopurine Disposition

Both TPMT and bioactivation enzymes found in hematopoietic cells; XO found only in the liver

Krynetski and Evans, Pharmacology 61:136-46, 2000

Common Impaired Function TPMT Alleles

•  Although there are over 15 different mutant alleles, only a few account for the majority of PM activity throughout the world; *3A more common in Caucasians, *3C in Asians and Africans.

These mutations affect the stability of the enzyme (enhanced proteasomal

degradation), with reduced steady-state Vmax and Clint

Protein t1/2 ~ 18 hr

Protein t1/2 ~ 0.25 hr

Concordance of TPMT Genotype and Phenotype

30

25

20

15

10

5

0

Figure 3. Thiopurine S-methyltransferase (TPMT) activity in patientswith different TPMT genotypes determined by mutation-specific poly-merase chain reaction methods.

Yates et alAnn Int Med 126(8):608-14, 1997

PM: 1/300 IM: 1/10

Clinical Pharmacogenetics Implementation Consortium (CPIC)

Relling et al, CPT 89:387-91, 2011.

•  Reduce dose to 1/10 that of normal and frequency to 3 times/week (vs daily) for low activity phenotype.

•  For intermediate activity phenotype, reduced dose by 30-50%.

Glucuronosyl Transferases (UGTs)

•  18+ different genes in humans Ø  UGT1A – 9 genes, 4 pseudogenes Ø  UGT2A (2 genes), 2B (7 genes) Ø  Membrane bound, ‘microsomal’ Ø  Catalyze the transfer of glucuronic acid to a ‘reactive’ heteroatom

(oxygen, nitrogen, sulfur) •  products - glucuronide conjugates- are readily excreted in urine and bile

•  UGT1 involved in endogenous bilirubin metabolism, and some xenobiotics; Ø  rare variants – Crigler-Najar Syndrome Ø  common variants à Gilbert’s (idiopathic hyperbilirubinemia)

•  UGT2 involved in steroid metabolism, phenolic xenobiotics (at least 7 forms)

Glucuronosyl Transferases

Guillemete, Pharmacogenomics J

(2003): 3, 136-158

UGT1A1 Variants •  There are 60+ unique variants in the UGT1A1 gene

•  4 are associated with a ‘mild phenotype’ Gilbert’s Syndrome – idiopathic hyperbilirubinemia

3 nonsynonymous (rare); 1 common and 2 rare promoter tandem TA repeats

Moderate decrease in function

•  24+ SNPs associated with severe phenotype 18 with Criglar-Najar Syndrome Type I 6 with Criglar-Najar syndrome Type II

Nonsynonymous or truncating; loss of function

UGT1A1 Polymorphism

•  Variable tandem repeat, (TA)5-8TAA, in the UGT1A1 promoter modulates gene transcription, protein expression and catalytic activity; 6 repeats – wild type.

•  Homozygosity for the (TA)7 allele, UGT1A1*28, associated with ~30% normal bilirubin conjugating activity – Gilbert syndrome (also 7/8 or 8/8 genotypes).

•  PMs: 10% allele frequency in Whites; 29-47%, African; 3%, Asians

VNTR

•  Undergoes ester hydrolysis (not all that rapid) to active SN-38, which in turn is detoxified by glucuronidation. Multiple UGTs catalyze the reaction (1A1, 1A9, 1A10), but 1A1 seems to dominate.

•  Although SN-38 is 1000x more potent Topo-I inhibitor than irinotecan, it circulates at levels 2-3% that of irinotecan and is more highly plasma protein bound (95% v 50%).

•  Parallel intestinal/hepatic CYP3A4 pathway and P-gp mediated efflux also significant.

•  Conversion of APC to SN-38 does not seem to occur (steric/polarity hindrance), although not tested rigorously.

Innocenti, DMD, 2001; PDR, 2004; Pauluzzi, J Clin Pharmacol, 2004’ Ohuri, Anticancer Res, 2004

P-gp

Association between UGT1A1*28 Genotype and Serum Bilirubin

Marcuello et al., Br J Cancer, 2004

Association Between UGT1A1*28 Genotype and Post-Irinotecan ANC Nadir

•  All grade 4 neutropenia (shaded area) occurred in patients carrying the UGT1A1*28 allele; ANC = absolute neutrophil count.

•  Exclusion of 7/7 genotype (10% of population) from standard dose would reduce frequency of grade 4 toxicity by 50%. Exclusion of anyone carrying a TA7 allele would eliminate such toxicity, but have poor positive predictive value.

Innocenti et al, J Clin Oncol, 2004

The Human GSTM1 Polymorphism

•  Gene deletion in GSTM1 allele •  42-55% of Caucasians are homozygous null •  Slightly higher in Asians, lower in Blacks •  Homozygotes for the active allele are rare •  Phenotype ---> TSO activity in WBC •  Genotyping analysis by PCR

GSTM1 null/non-null gene locus

Xu et al., JBC 1998

Simplified overview of benzo[a]pyrene biotransformation

benzo[a]pyrene (+)-benzo[a]pyrene-7,8- oxide

(-)-benzo[a]pyrene-7,8- dihydrodiol

(+)-benzo[a]pyrene-7,8- dihydrodiol-9,10-epoxide

CYP1A1

CYP1A1

mEH

DNA reactive;!lung and skin tumors !

Inactive products

GSTM1 and Lung Cancer •  Meta analysis yielded OR of 1.41

- 1593 cases, 2135 controls ��� - 95% CI 1.23 - 1.61, p<0.0001

•  Estimated attributable risk, 17% •  No large differences with histological type���

- squamous 1.49 (1.22-1.80, n=591)��� - adenocarcinoma 1.53 (1.26 - 1.85, n=482)��� - small cell carcinoma 1.90 (1.27-1.85, n=122)

•  Most recent meta analysis (2015) found OR = 1.46

From: McWilliams et al., Cancer Epi Biomark Prev 4: 589-94, 1995 Smith et al, – Polymorphisms in Xenobiotic Conjugation, IN: Gene-Environment Interactions, Chp 8, Wiley Press, 2006 Yang et al., Sci Rep. 2015, 23;5:9392. "

GSTM1 and Lung Cancer Risk- Biological Plausibility?

Supportive: Some activity toward PAH epoxides High amounts in liver, site of much

activation Smokers’ urine more mutagenic in

GSTM1 null Lymphocyte SCE increased in GSTM1

null smokers Interaction with CYP1A1

Not Supportive Very low UGTM1 expression in lung Activity toward BPDE low, compared with GSTP1 Inconsistencies in results across many studies Association evident in adenocarcinoma

Genetic Variation and Rare ADRs

Characteristic Type A Type B

Dose dependent generally yes no clear relationship

Predictable from known pharmacology

yes no

Animal models usually predictable none known

Frequency/severity common/variable rare/severe

First detected Phase I-III Phase IV (post approval)

Pirmohamed, AAPS Journal 8:E20-26, 2006

Hepatic and Idiosyncratic Drug Toxicities

•  Because the liver is the dominant site of biotransformation, it is also highly susceptible to metabolically-based toxicity, including immune-based toxicity.

Drug Indication Active Metabolite Toxicity

Chloramphenicol Antimicrobial - restricted Acyl chloride Hematopoietic ToxicityAcetaminophen Analgesia Quinoneimine HepatotoxicityNSAIDS (zomepirac) Inflammation Acyl glucuronides AnaphylaxisPhenytoin Epilepsy Arene oxides Stevens-Johnson, SLEHalothane Anesthesia Trifluoroacetic acid Mild & Severe HepatitisFelbamate Epilepsy - restricted Conjugated alkene HepatotoxicityValproic Acid Epilepsy Acyl CoA HepatotoxicityTiclopidine Antiplatelet - monitored Oxidized thiophene Blood dyscrasiasClozapine Antipsychotic Conjugated imminium ion AgranulocytosisFlutamide Prostate CA - monitored Nitroaromatic HepatotoxicityTolcapone Parkinson’s-monitored Nitroaromatic HepatotoxicityTrovofloxacin Antibiotic - restricted Aminopiperidine oxidation HepatotoxicityTroglitazone Antidiabetic - withdrawn Quinone methide HepatotoxicityZileuton Antiasthmatic-monitored ? HepatotoxicityAbacavir HIV Infection -restricted Carbovir triphosphate Hypersensitivity

Representative drugs that cause severe toxicities

Drug Activation Detoxification Neoantigen Formation Neoantigen Peptide Processing Binding of Antigenic Peptide to HLA Peptide Presentation of Complex T-Helper Cell Recruitment Activation of Killer T-cells or B-cells

P450

(covalent binding in target cell)

(in target cell or APC cell?)

(in APCs; e.g., Kupffer cells)

GST

(to APC cell surface for T-cell recognition)

Target Cell Death

HLA Genotype Dependent

Proposed Hypersensitivity Reaction Mechanism

Abacavir Hypersensitivity

•  Nucleoside analog reverse transcriptase inhibitor used in combination therapy to treat HIV-1 infection

•  About 5-8% of treated patients will develop a multi-system hypersensitivity reaction, which can be fatal.

•  Indications of MHC Gene Involvement: Ø Develops within 6 wks or rarely at all Ø Racial differences in risk (decreased risk in black population) Ø Familial predisposition Ø Evidence for neoantigen formation (haptenation) or direct binding

to MHC

Association of Abacavir Hypersensitivity with HLA Genotype

•  Lancet 359:727-32, 2002

•  Lancet 359:1121-2, 2002 (GSK Group)

Loci AbacavirHypersensitive

(n = 18)

AbacavirTolerant(n = 167)

Odds Ratio(95% CI)

Pc

HLA-B*5701 14 (78%) 4 (2%) 117 (29-481) < 0.0001

HLA-DR7, HLA-DQ3

13 (72%) 6 (3%) 73 (20-268) < 0.0001

HLA-B*5701, HLA-DR7, HLA-DQ3

13 (72%) 0 (0%) 822 (43-15,675) < 0.0001

Caucasoids

Loci Cases Controls Odds Ratio

HLA-B57 36/65 (55%) 2/80 (3%) 23.6 (8.0-70.0)

HLA-B*5701 36/65 (55%) 1/80 (1%)

HLA-B*5701 and HLA-DR7 15/46 (33%) 1/69 (1%)

GSK group also, reported a significant association with CYP1A2 and TNFα SNPs

Screening for HLA-B*5701 Eliminates the Risk for Abacavir Hypersensitivity (Diagnosis Confirmed by Patch Testing)

Screened Control

Total Population Caucasians

Inci

denc

e of H

yper

sens

itivi

ty

Rea

ctio

n (%

)

0

1

2

3

4

5

2.7% 3.1%

Mallal et al. NEJM 358:568-579, 2008

0% 0%

Negative predictive value = 100% Positive predictive value = 48%

Carbamazepine and Phenytoin Immunotoxicity

•  Established drugs used to treat epilepsy (CBZ also used for other disorders) •  Associated with adverse reactions, many of which occur in the skin:

Mild maculopapular exanthema (16% of patients) Severe cutaneous reactions (Stevens-Johnson syndrome; SJS); 1:10,000 - 90% cases

occur within first 2 mo of therapy Toxic epidermal necrolysis (TEN, 40% fatal)

•  Multiple studies have found a strong association between the HLA-B*1502 gene and SJS/TEN with CBZ use in Han Chinese

Chung et al, Nature 428:486, 2004 Man et al, Epilepsia 48:1015-18, 2007

Hung et al., Pharmacogenetics and Genomics 16:297-306, 2006

•  A similar association between the HLA-B*1502 gene and SJS/TEN with DPH use in Han Chinese and Thai

Locharernkul et al, Epilepsia 49:2087-91, 2008 Man et al, Epilepsia 48:1015-18, 2007

Anti-Epileptic Drug Immunotoxicity

•  FDA has relabeled Carbamazepine (Tegretol) and Phenytoin (Dilantin) to recommend HLA testing in high risk populations

Warning Serious Dermatological Reactions and HLA-B*1502 Allele

… Patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment

with Tegretol. Patients testing positive for the allele should not be treated with Tegretol unless the benefit clearly outweighs the risk