HLA Pharmacogenetics and Cutaneous Adverse Drug Reactions PDF

HLA Pharmacogenetics and Cutaneous Adverse Drug Reactions Bojana Stevich-Heemer, MS, PharmD, MEd, BCOP  Objectives Present importance of human leukocyte antigen (HLA) pharmacogenetics Evaluate relationship between HLA and cutaneous adverse reactions and present how...

HLA Pharmacogenetics and Cutaneous Adverse Drug Reactions Bojana Stevich-Heemer, MS, PharmD, MEd, BCOP  Objectives Present importance of human leukocyte antigen (HLA) pharmacogenetics Evaluate relationship between HLA and cutaneous adverse reactions and present how HLA function in pathogenesis of serious cutaneous adverse drug reactions Present application of HLA genotypes in clinical practice  Human Leukocyte Antigen (HLA) Human Leukocyte Antigen (HLA) exhibits genetic polymorphism There are two classes of HLA: – Class I and – Class II Function of HLA: to present peptides from pathogen to T cells to start immune response Bertino J. et. al. Pharmacogenomics: An Introduction and Clinical Perspective. (2013))  Human Leukocyte Antigen (HLA) Due to biology and polymorphism of HLA there are different diseases that have been associated with different HLA types Also, there are explained relationships between HLA types and development and progression of different autoimmune diseases Bertino J. et. al. Pharmacogenomics: An Introduction and Clinical Perspective. (2013))  Human Leukocyte Antigen (HLA) There have been identified risks of hypersensitivity reactions to specific medications and HLA types including: – Abacavir (HLA-B) – Allopurinol (HLA-B) – Carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B) – Phenytoin (HLA-B) Bertino J. et. al. Pharmacogenomics: An Introduction and Clinical Perspective. (2013)) DiPiro et. al. (2020). Chapter e6: Pharmacotherapy: A Pathophysiologic Approach, 11th ed. https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines at: https://cpicpgx.org/guidelines/  Human Leukocyte Antigen (HLA) Some of these hypersensitivity reactions include: – Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Bertino J. et. al. Pharmacogenomics: An Introduction and Clinical Perspective. (2013)) DiPiro et. al. (2020). Chapter e6: Pharmacotherapy: A Pathophysiologic Approach, 11th ed.  Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) – Severe skin reaction overall Stevens-Johnson syndrome (SJS): less severe Toxic Epidermal Necrolysis (TEN): more severe – Often triggered by a medication – Often starts with fever and flu-like symptoms https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis/  Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) – Within few days skin starts to blister – There might be formation of skin erosions – Can cause damage to mucous membranes – Severe damage to skin and mucous membranes can cause life-threatening disease https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis/  Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) can cause: – Different complications including: pneumonia, infections, shock, multiple organ failure, death – Long-term effects including: changes in skin, dryness of skin and mucous membrane, excess sweating, hair loss, impaired taste, difficulty urinating, and others https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis/  Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN): – Process of SJS/TEN is not well understood – Data from different studies suggest that HLA-B gene variations associated with SJS/TEN can cause immune system to react with specific medications https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis/  Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN): – Medications can cause immune T cells and natural killer (NK) cells to release substance granulysin which can destroy cells in skin and mucous membrane https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis/  Abacavir Abacavir: – Medication used for treatment of HIV – Nucleoside reverse transcriptase inhibitor Inhibits viral reverse transcriptase, suppresses HIV ability to convert its RNA genome into DNA before insertion into host cell’s genome – About 5-8% of patients can experience hypersensitivity reactions (HSRs) if genetically- guided therapy is not used Martin MA et. al. Clinical Pharmacology and Therapeutics 2012.  Abacavir Abacavir: – Hypersensitivity reactions (HSRs) include different symptoms including: fever, rash, nausea, vomiting, abdominal pain, fatigue, dyspnea – Drug re-challenge contraindicated – Hypersensitivity reaction associated with HLA- B*57-01 allele Martin MA et. al. Clinical Pharmacology and Therapeutics 2012.  Abacavir Abacavir: – Genotype with absent HLA-B*57-01 called negative on genotype test and associated with low risk of hypersensitivity reaction Identified in about 94% of patients – Genotype with presence of at least one HLA-B*57- 01 called positive on genotype test and associated with high risk of hypersensitivity reaction Identified in about 6% of patients Martin MA et. al. Clinical Pharmacology and Therapeutics 2012.  Abacavir Abacavir: – Carrier of HLA-B*57-01: Increased risk of HSRs Abacavir not recommended – Non-carrier of HLA-B*57-01: Low or reduced risk of HSRs Use of abacavir recommended per standard dosing guidelines Martin MA et. al. Clinical Pharmacology and Therapeutics 2012.  Allopurinol Allopurinol – One of common causes of severe cutaneous adverse reactions (SCARs) – SCARs can include: Drug hypersensitivity syndrome Stevens-Johnson syndrome Toxic epidermal necrolysis – Can also cause less severe rash unassociated with systemic symptoms or organ damage Hershfield MS et. al. Clinical Pharmacology and Therapeutics 2013.  Allopurinol Allopurinol – Analog of purine-based hypoxanthine – Inhibits conversion of hypoxanthine and xanthine to uric acid by xanthine oxidase – FDA approved in 1966 for treatment of gout, inflammatory arthritis caused by intra-articular monosodium urate crystals – Goal of therapy to keep serum and plasma urate level 3 months cautiously continue carbamazepine since the incidence of HSRs highest during the first 3 months of carbamazepine therapy Phillips EJ et. al. Clinical Pharmacology and Therapeutics. 2018. CPIC Recommendations for Carbamazepine Based on HLA-B and HLA-A Genotypes HLA-B*15-02 positive and any HLA-A*31-01 – Greater risk of carbamazepine-induced SJS/TEN – If carbamazepine-naïve do not use carbamazepine – If patient already has been taking carbamazepine for >3 months cautiously continue carbamazepine since the incidence of SJS/TEN highest during the first 3 months of carbamazepine therapy Phillips EJ et. al. Clinical Pharmacology and Therapeutics. 2018. CPIC Recommendations for Oxcarbazepine Based on HLA-B Genotypes HLA-B*15-02 negative: – Normal risk of oxcarbazepine-induced SJS/TEN Use oxcarbazepine per standard dosing guidelines Phillips EJ et. al. Clinical Pharmacology and Therapeutics. 2018. CPIC Recommendations for Oxcarbazepine Based on HLA-B Genotypes HLA-B*15-02 positive: – Increased risk of oxcarbazepine-induced SJS/TEN If oxcarbazepine naïve → Do not use oxcarbazepine If patient already has been taking oxcarbazepine for >3 months cautiously continue oxcarbazepine since the incidence of SJS/TEN highest during the first 3 months of oxcarbazepine therapy Phillips EJ et. al. Clinical Pharmacology and Therapeutics. 2018.  Phenytoin and Fospheytoin Phenytoin and fosphenytoin (prodrug of phenytoin) → Used for treatment of focal and generalized convulsive status epilepticus Phenytoin indicated for: – Control of generalized tonic-clonic and complex partial seizures – Prevention and treatment of seizures occurring during or after neurosurgery Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin Narrow therapeutic index Higher plasma concentrations increase risk of toxicity Non-linear saturable pharmacokinetics CYP2C9 autoinduction – CYP2C9 pharmacogenetics Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin Based on CYP2C9 phenotype can be: – Normal metabolizers: has two normal function alleles – Intermediate metabolizers: One normal function allele and one decreased function allele OR One normal function allele and one no function alleles OR Two decreased function alleles Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin Based on CYP2C9 phenotype can be: – Poor metabolizers: One no function allele and one decreased function allele OR Two no function alleles Variant of HLA-B*15-02 associated with increased risk of SJS and TEN Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin If HLA-B*15-02 positive: – If phenytoin-naïve → Do not use phenytoin – If previously on phenytoin for >3 months → cautiously use phenytoin in future since the incidence of SJS/TEN highest during the first 3 months of phenytoin therapy Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin If HLA-B*15-02 negative and CYP2C9 normal metabolizer: – No specific adjustment needed from typical dosing If HLA-B*15-02 negative and CYP2C9 intermediate metabolizer: – Activity Score 1.5: No specific adjustment needed from typical dosing – Activity score 1.0: First dose use typical initial or loading dose, subsequent dose use 25% less than typical maintenance dose Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021  Phenytoin and Fospheytoin If HLA-B*15-02 negative and CYP2C9 poor metabolizer: – First dose use typical initial or loading dose – Subsequent dose use 50% less than typical maintenance dose Karnes JH et. al. Clinical Pharmacology and Therapeutics. 2021 Practice Questions  Practice Question 1 Based on CYP2C9 phenotypes patients taking phenytoin can be: a) Normal metabolizers, intermediate metabolizers, or poor metabolizers b) Normal metabolizers and poor metabolizers but not intermediate metabolizers c) Intermediate metabolizers and poor metabolizers but not normal metabolizers  Practice Question 1 - Answer Based on CYP2C9 phenotypes patients taking phenytoin can be: a) Normal metabolizers, intermediate metabolizers, or poor metabolizers b) Normal metabolizers and poor metabolizers but not intermediate metabolizers c) Intermediate metabolizers and poor metabolizers but not normal metabolizers  Practice Question 2 Which of the following HLA-B variants has been associated with increased risk of Stevens- Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and phenytoin use? a) HLA-B*15-02 c) HLA-B*57-01 d) HLA-B*58-01  Practice Question 2 – Answer Which of the following HLA-B variants has been associated with increased risk of Stevens- Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) and phenytoin use? a) HLA-B*15-02 b) HLA-B*57-01 c) HLA-B*58-01  Practice Question 3 If a patient has hypersensitivity reactions (HSRs) to carbamazepine that may predispose patient to hypersensitivity reactions (HSRs) to oxcarbazepine. a) True b) False  Practice Question 3 – Answer If a patient has hypersensitivity reactions (HSRs) to carbamazepine that may predispose patient to hypersensitivity reactions (HSRs) to oxcarbazepine. a) True b) False  Practice Question 4 Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) can cause severe damage to skin and mucous membranes which can cause life-threatening disease. a) True b) False  Practice Question 4 – Answer Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) can cause severe damage to skin and mucous membranes which can cause life-threatening disease. a) True b) False  Questions? Email: [email protected]  References Bertino JS, DeVane CL , Fuhr U, AD Kashuba AD, Ma JD. Immunology, Transplantation, and Vaccines chapter (chapter 15). Pharmacogenomics: An Introduction and Clinical Perspective. 2013. McGrawHill. Available in AccessPharmacy. DiPiro et. al. Pharmacogenetics chapter (chapter e6), Pharmacotherapy: A Pathophysiologic Approach, 2020. 11th ed. Available in AccessPharmacy. Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines at: https://cpicpgx.org/guidelines/ Accessed 3/1/2021 Hershfield MS, Callaghan JT, Tassaneeyakul W, et. al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotypes and Allopurinol Dosing. Clinical Pharmacology and Therapeutics 2013; Feb;93(2):153-8. doi: 10.1038/clpt.2012.209.  References Karnes JH, Rettie A, Somogyi AA et. al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical Pharmacology and Therapeutics. 2021; Feb;109(2):302-309. doi: 10.1002/cpt.2008. Martin MA, Klein TE, Dong, BJ et. al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotypes and Abacavir Dosing. Clinical Pharmacology and Therapeutics 2012; Apr; 91(4): 734–738. doi: 10.1038/clpt.2011.355 Phillips EJ, Sukasem C, Whirl-Carrillo, et. al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA Genotypes and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clinical Pharmacology and Therapeutics. 2018; Apr;103(4):574-581. doi: 10.1002/cpt.1004. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. U.S. Department of Health and Human Services National Institute for Health. Available at: https://medlineplus.gov/genetics/condition/stevens-johnson-syndrome-toxic- epidermal-necrolysis/ Accessed 3/1/2021