Anti-infective Pharmacogenomics Flashcards
What are the intrinsic factors that influence variable drug response
Pharmacogenomics
Age (peds/geriatrics)
Gender
Body weight
Concurrent illnesses (renal/ hepatic)
What are the extrinsic factors that influence variable drug response
Concurrent medications (DDI)
alcohol consumption
Adherence
Lifestyle factors (diet, exercise, smoking)
Genetic variability can influence various enzyme that categorized into gene involved in
Pharmacokinetics
Pharmacodynamics
Off target proteins
Pharmacokinetics
Proteins related to pharmacokinetics participate in ADME
Pharmacodynamics
Proteins are directly associated with the drug target such as receptors
Off target proteins
Proteins that are not directly linked to the drugs ADME or primary target yet can influence the drugs response.
Goals of pharmacogenomicics in ID
Improve drug efficacy (optimal dosing)
Minimize risk of adverse effects (avoid drug toxicity)
Predict treatment failure due to anti-infective resistance
PGX does NOT replace therapeutic use T/F
True
What are the two types of genomics in the ID world
Host genomic
Microbial/viral genomics
Host genomics
Genetic predisposition to drug toxicity
Genetic predisposition to significantly change drugs metabolism
Microbial/viral genomics
Rapidly replicated increases probability of mutation and development of drug resistance
What class of antibotic is included in the CPiC medication guidelines
Aminoglycosides
-Amikacin
-Gentamicin
-Plazomicin
-Tobramycin
some gram of positive, mostly gram negative
What is the MOA of aminoglycoside
Disrupt protein synthesis by irreversibly binding to 16s of ribosome complex
What is the adverse effect associated with aminoglycoside? What is the vareient associated if any?
Nephrotoxicity
Ototoxicity
-MTXRNR1 = higher risk
Where does the MT-RNR1 gene reside and also known as ?
Human mitochondrial genome
Mitochondrially encoded 12s ribosomal RNA
Genetic alterations in MTRNR1 gene is associated with
Predisposition to aminoglycoside induced hearing loss
Genetic alteration in MTRN1 causes 12s rRNA subunit protein to more closely resemble the bacterial 16s rRNA subunit —>
Increase aminoglycoside off target binding
MTRNR1 increased risk hearing loss CIPC recommendation
Very high risk
Avoid aminoglycoside antibiotics unless the high risk of permanent hearing loss is outweighed by the severity of the infection and lack of saf or effective alternative
MTRNR1 normal risk hearing loss CIPC recommendation
Normal risk
Use aminoglycoside antibiotics at standard doses for the shortes feasible course with therapeutic dose monitoring
Evaluate regularly for hearing loss
MTRNR1 uncertain risk hearing loss CIPC recommendation
Weak or no evidence for MT RNR1
Use aminoglycoside antibiotics at standard doses for the shortes feasible course with therapeutic dose monitoring
Evaluate regularly for hearing loss
What should you do if there is no effective alternative to an aminoglycoside antibiotic available
Evaluate for hearing loss frequency during therapy
What antifungal medication has a CPIC recommendation?
Voriconazole
Indication of voriconazole and MOA
Invasive aspergillosis
It impairs fungal growth and proliferation by weakening the fungal cell membrane
Inhibits CYP450 14 a-demethylase , disrupting estrogterol synthesis in fungi
What is the gene of interest for voriconazole for the CIPIC guidelines
CYP2C19
Voriconazole adverse effects
Hepatotoxicity
Neurotoxicity
Visual hallucinations
Encephalopathy
Neuropathy
Photopsia
Rash
Photosensitivity
Periostitis
What therapeutic concentration rand of voriconazole should be measured after steady state is achieved?
Cmin/ trough
Invasive aspergillosis:1-5 ug/ml
Individual that metabolizes voriconazole efficiently are at risk for
Treatment failure bc of low trough levels (<0.5) —> sub therapeutic
Extentsiom of hospital stay
Individual that are NOT able to metabolizes voriconazole efficiently are at risk for
Adverse drug reactions , trough concentration >5-5.5 mg/L —> Supratherapeutic
Hepatotoxicity
Neurotoxicity
Visual hallucinations
CYP2C19 ultra rapid metabolized
An individual carrying two increased function alleles
CYP2C19 rapid metabilzer
An individual carrying one normal function allele and one increases function allele
CYP2C19 normal metabilizer
Individual carrying two normal function alleles
CYP2C19 intermediate metabilizer
An individual carrying one normal function allele and one no function allele or
one no function allele and one increased function allele
CYP2C19 poor metabilizer
Carrying two no function allele
Voriconazole dosing recommendations for Ultra rapid and rapid metabolizers
Consider an alternative antifungal agent not affected by CYP2C19 variations
Isavuconazole
Posaconazole
Liposomal amphotericin B
Potential SUBtheraputic levels
Voriconazole dosing recommendations for poor metabolizers
Consider an alternative antifungal agent not affected by CYP2C19 variations
Isavuconazole
Posaconazole
Liposomal amphotericin B
Avoid ADR
Potential SUPRAtherapeutic levels
What three antiviral medications has CIPIC recommendations
Atazanavir (protease inhibitors)*
Abacavir (NRTIs)*
Efavirenz
What are we concerned with abacavir and what gene/allele is associated with it?
Hypersensitivity reaction
HLAB*57:01
What is the sensitivity observed with abacavir associated with
Individual gene factors that increase hypersensitivity reactions
HLA-B*7:01
What is abacavir’s hypersensitivity associated with
Off target effect
CPIC recommendation for abacavir who is a carrier of HLA-B*57:01
Significantly increased risk of hypersensitivity
Abacavir not recommended
CPIC recommendation for abacavir who is a NONcarrier of HLA-B*57:01
Low or reduced risk of hypersensitivity
Use abacavir per standard dosing guidelines
What is the concern for atazanavir and what is the gene of interest?
Hyperbillirubinemia
UGT1A1 (phase ll )
What factors increase risk for hyperbilirubinemia
Decrease UGTA1A1 production or function
DDI: inhibition of UGT1A1 (ABACTAVIR).
What is atazanavir effect?
Off target effect
UGT1A1 DOES NOT contribute to metabolism nor PD
Recommendation for UGT1A1 for normal/extensive and intermediate metabolizers
No need to avoid atazanavir
Recommendation for UGT1A1 for poor metabolizers
Consider alternative agent particularly where jauis of concern to patient
