PDTI Modules 11,12

Aminoglycosides in Infants and Children

• Infants and children have higher volumes of distribution, leading to lower plasma concentrations of aminoglycosides.
• Due to the increased distribution, aminoglycosides remain in the body longer, which necessitates longer dosing intervals to prevent accumulation and potential toxicity.
• A higher loading dose might be needed in infants and children to achieve similar plasma concentrations as adults.

Creatinine Clearance Calculation

• A 90-year-old male, weighing 80 kg and 6’3’’ tall, with a serum creatinine level of 1.2 mg/dL, has a creatinine clearance of 46.3 mL/min.
• Creatinine clearance is calculated using the Cockcroft-Gault equation: CrCl = \frac{(140 - \text{Age}) \times \text{Weight (kg)}}{72 \times \text{Scr (mg/dL)}}

Phase I Metabolic Enzymes

• Phase I drug-metabolizing enzyme activity is minimal or absent at birth.
• In children, Phase I enzyme activity can exceed adult levels as maturation occurs.

Thiopental Distribution in Elderly

• Elderly individuals typically have a higher body fat percentage than younger adults.
• The higher body fat in the elderly results in increased distribution of highly lipid-soluble drugs like thiopental.

Cockcroft-Gault Method

• The Cockcroft-Gault equation has been widely used for dosing guidance in patients with impaired renal function.
• The MDRD eGFR equation is now increasingly used for clinical assessments of renal function.

Considerations for Obese Patients

• Obese patients may experience an elevated risk of nephrotoxicity if dosing of weakly or moderately lipophilic drugs is based on actual body weight.
• Increased cardiac output and blood volume in obesity can change drug distribution patterns.
• Using ideal body weight for aminoglycosides may decrease exposure, reducing therapeutic efficacy in obese patients.
• Adjusted body weight is usually used when dosing aminoglycosides in obese patients.

Body Surface Area (BSA) Estimation

• The estimated body surface area (BSA) for a 100 kg patient is 2.22 m².
• BSA can be estimated using the formula: BSA (m2)=Weight (kg)×Height (cm)3600BSA , (\text{m}^2) = \sqrt{\frac{\text{Weight (kg)} \times \text{Height (cm)}}{3600}}

Creatinine Clearance Estimation

• A 34-year-old, 5'10'', 82 kg patient with a serum creatinine of 1.5 mg/dL has an estimated creatinine clearance of 80 mL/min.
• Creatinine clearance is calculated using the Cockcroft-Gault equation: CrCl=(140−Age)×Weight (kg)72×Scr (mg/dL)CrCl = \frac{(140 - \text{Age}) \times \text{Weight (kg)}}{72 \times \text{Scr (mg/dL)}}

Drug Response and Genotype

• A patient with a drug metabolism genotype of V/V and a drug receptor genotype of WT/V is expected to have about 40% efficacy and high toxicity (80%) at a normal dose.

Central Dogma of Molecular Biology

• Multiple RNA transcripts can be made from one stretch of DNA (gene), and multiple proteins can be made from each RNA transcript.
• DNA flows to RNA through transcription, and RNA flows to protein through translation.

Intronic SNPs

• A SNP located in the intronic region of a gene is most likely to affect the splicing of the gene and lead to a change in the mRNA.

Hardy-Weinberg Equilibrium

• If SNP WOW has allele frequencies of A=0.70 and C=0.30, the expected genotype frequencies in Hardy-Weinberg equilibrium are AA=0.49, AC=0.42, CC=0.09.
• The Hardy-Weinberg equation is: p² + 2pq + q² = 1.

Linkage Disequilibrium

• Investigators assessing what alleles in GALNT2 are inherited together, for a candidate gene for plasma HDL cholesterol levels are looking at Linkage Disequilibrium.

Pharmacogenomic Testing

• Turnaround time is a feasibility issue in pharmacogenomic testing; for example, a genetic test with a two-week turnaround when the drug prescription is needed within three days.

Pharmacogenomic Study Design

• The first step in designing a pharmacogenomic study is a literature review using PubMed.

Resources for Drug Pathways and Guidelines

• PharmGKB is the best resource for drug pathway searches and pharmacogenomic guidelines.

Clinical Significance of Genetic Variations

• NCBI ClinVar provides information on variants with clinical significance.

Haplotype Possibilities

• The number of possible haplotypes is calculated as 2ⁿ, where N is the number of SNPs.
• Three SNPs in PROX1 could have 8 possible haplotypes.

Allele Frequencies Across Populations

• The 1,000 Genomes Project is the best resource for determining if a genetic variant is common in a specific patient population.

Challenges with Pharmacogenomic Testing

• Challenges with pharmacogenomic testing include provider knowledge, test turnaround time, and insurance coverage.

CYP2C19 Diplotype

• A patient is considered *3/*3 if they have two variant alleles at rs4986893 (*3) and reference alleles for the other SNPs.

Linkage Disequilibrium (LD) Value

• An r² value of 0.1 for two SNPs indicates low linkage disequilibrium, meaning they are not likely inherited together.

Hardy-Weinberg Equilibrium Genotype Frequencies

• If SNP GATOR has allele frequencies of A=0.75 and C=0.25, the expected genotype frequencies are AA=0.56, AC=0.38, CC=0.06.

CPIC Guidelines

• A key assumption of the CPIC guidelines is that the patient’s genotype information is already known i.e., the guidelines do not recommend genetic testing.
• CPIC guidelines provide recommendations based on available genetic data but do not advise on testing.

Omics Technology

• Oncotype DX® tests are based on transcriptomics because they analyze gene expression profiles.
• The Prostarix™ test is based on metabolomics as it measures the concentration of several metabolites.

Pharmacogenetics

• Variations in drug targets and drug-metabolizing enzymes impact the pharmacodynamics of medications, which can result in variability in effectiveness or toxicity.
• Variations in drug-metabolizing enzymes can result in an increased amount of active drug in an individual’s body.

Protein-Coding DNA

• The protein-coding part of our DNA is known as exons, and it makes up approximately 2% of our entire genome.

Polymorphism Type

• A non-synonymous (or missense) SNP polymorphism occurs when a point variation results in an alternative amino acid being coded, leading to a different protein.

Genetic Terminology

• One *# is referred to as an allele.
• A diplotype is composed of two alleles inherited from each parent, and it determines the phenotype.

Phenotype Representation

• Phenotypes range from poor to ultra-rapid metabolizers, corresponding to varying enzyme activity levels.

CPIC Level

• A provisional CPIC level means a guideline has not been completed yet.
• Section 2 of the FDA table indicates potential safety or response impacts.

Metabolizer Phenotypes

• A normal metabolizer has the highest elimination rate, lowest Cmax and AUC, and the earliest Tmax compared to poor or intermediate metabolizers.

Benefits of Pharmacogenetic Testing

• Pharmacogenetic testing helps optimize treatment by improving drug selection, reducing side effects, and lowering healthcare costs.

Major Omics Fields

• Gene – genomics
• mRNA – transcriptomics
• protein – proteomics
• metabolite – metabolomics