MD315 - T9 - Phramacogenetic and Gene Therapy

Pharmacogenetic - Goal

Lower Toxicity and Increase Drug Efficacy

Pharmacogenetic - Uses

In narrow therapeutic index drug, predict clinical outcome of antitumor therapy

KRAS mutation - effect 

KRAS stays active without EGFR → Cell proliferation, angiogenesis, metastasis continues

KRAS mutation - Drug

Cetuximab Resistance 

Cetuximab - MoA 

Monoclonal antibodies → Blocking EGFR receptor

Type A, Predictable - ADR

Overdose, Side effect, drug interactions

Type B, Unpredictable - ADR

Intolerance, Idiosyncrasy, Drug Hypersensitivity (allergy)

Type A - reaction

can predicted from knwon pharmacology of the drug, dose dependent, common ADR

Type B - Reaction

Dose independent and rarely happen

Pharmacokinetics of drugs - Mech **

Absorption, Distribution, Metabolism, Excretion

Drug Metabolism - Phase 1 - Description

CYP450 enzyme, Polar functional group to drug

Drug Metabolism - Phase 2 - Description

UGT enzyme, Make drug soluble 

Risperidone - Gene and Drug Type

CYP2D6, Antipsychotic

Efavrirenz - Gene and Drug Type

CYP2B6, Antiretriviral Agent

Capecitabine, 5-Fluorouracil - Gene and Drug Type

DYYD, Colorectal cancer, Gastric Cancer

Mercaptopurine - Gene and Drug Type

TMPT, Acture Lymphocytic Leukemia

Risperidone - ADR

Weight Gain, Increase Prolactin Level

Risperidone, CYP2D6*1 - Metabolism and ADR 

Normal, Normal ADR 

Risperidone, CYP2D6*10 - Metabolism and ADR 

Decrease Enzyme Activity, Increase Drug Concentration, Increase Insulin Resistance → Increase ADR (weight gain, prolactin)

Efavirenz - ADR 

Neurologic and Neuropsychiatric Effects

Efavirenz, CYP2B6*6 - Metabolism and ADR 

Decrease Enzyme Activity, Increase Drug Concentration in Blood → Increase Neurotoxic Effect

Capecitabine, 5-FU - Metabolism

By Dihydropyrimidine dehydrogenase (DPYD), 80 - 90% turned inactive normally 

5-FU, DPYD*2A - Metabolism and ADR 

Rate-limitng enzyme that catabolize 5-FU, 80% to 90% inactivated -

5-FU, DPYD*2A - Metabolism and ADR 

Loss of DPYD, Drug Accumulates, Severe neutropenia and Severe Diarrhea - life threatening

5-FU - Gene Score - 2.0

DPYD1/1, normal metabolizer, 100% drug

5-FU - Gene Score - 1.0

DPYD2A/1, DPYD13/1, Intermediate metabolizer, 50% drug

5-FU - Gene Score - 1.5

DPYP*1/HapB3, Intermediate metabolizer, 50% Drug

5-FU - Gene Score - 0.0

DYPD2A/13, Poor Metabolizer, Avoid 5-FU 

Uracil and DPYD - normal physiology

DPYD also breaks down uracil, uracil used as marker

Uracil - between 16 and 150 ng/ml - Action

Decrease dose of 5-FU, 20-30% of the normal dose 

Uracil - above 150 ng/ml - Action

Stop 5-FU, completely deficient patient

5-FU - ADR in general

neutropenia and diarrhea 

DPYP Genetic Test V. Phenotypic Test

Pathogenic DYPD variant v. Actual enzyme variant (uracil concentration and DPD activity)

Severe Cutaneous Adverse Reaction - Description

Type 2, Allergy, Life threatening, SJS

HLA-B*15:02 - Drugs and Treats

Carbamazepine, Oxcarbazepine - Antiepileptic Drug 

HLA-B*58:01 - Drugs and Treats

Allopurinol - Gout 

HLA-B*57:01 - Drugs and Treats

Abacavir - HIV-1 

HLA - Gene location

Class I, Short Arm of Chromosome 6

What happens in SCARs? 

Drug Bind to the HLA region → i.e. allopurinol to HLA-B*58:01 → Massive Cytokine activation → toxic → damage to keratinocyte

Gene therapy - how

altering gene in virus and let virus attack