PK/PD - Pediatrics Flashcards
Age Classifications
Neonates: Newborn to 1 month Infants: 1 month to 2 years Children: 2 years to 12 years Adolescents: 12 to 16 years old **FDA established**
Pregnancy Classifications
Term Pregnancy: 37-40 weeks
Premature Pregnancy: < 37 weeks
Viable Pregnancy: > 24 weeks
Age Classfications
Gestational Age: Time of conception to birth
Postnatal Age: Age since birth
Postmenstrual Age: GA + PNA
Weight Classifications
Low Birth Weight: < 2500 g: < 35 weeks
Very Low Birth Weight: < 1500 g: < 30 weeks
Extremely Low Birth Weight: < 1000 g: < 27 weeks
Fetal Development
- Embryonic Periods: organogenesis, sensitivity to drug exposure
- Fetal Periods: organ maturation, less sensitive to drug exposure but still significant
- *Can affect PK**
Liver Development
- CYP content ~30-60% of adult values
- Starts developing around week 4 and continues to develop throughout gestation
Renal Development
- Develops weeks 5-15
- Development continues until completed at week 24
- Functionally matures at birth - can be affected by utero drug exposure
Milestones
- Weight: doubles in 1st 6 months, triples by first year
- Body composition: fat, protein, water percentage are constantly changing
- Organ maturation: major organs mature in the first 2 years
Pediatric PK Considerations
ADME parameters vary greatly by age, even when normalized by weight
Pediatric PD Considerations
Some evidence supports differing receptor sensitivity and density
PK - Absorption
- Total absorption is driven by the rate (affects onset) and extent (determines effective dose) of absorption
- Drug enters body for therapeutic effects at oral/GI, transmucosal, transdermal, and IM routes
- Matters since body composition and development stages affect absorption
Absorption - Oral/GI - pH
Normal Adult pH: 1.5-3.5
Birth d/t amniotic fluid pH: 6-8
24-48 hours pH: 1-3
Day 8 pH: ~7
Absorption - Oral/GI - Secretions
-HCl secretions mature slowly
-Reaches adult levels at about 2 years of age
-Every drug is optimally absorbed or activity at certain pH
EX: beta lactam antibiotic: high pH: high bioavailability
EX: Weak acids (APAP, Phenytion): high pH: low bioavailability
Absorption - Oral/GI - Gastric Motility/Emptying
-Small intestine = major site of absorption
-Prolonged in neonates which affects the rate of absorption
EX: APAP, digoxin has delayed onset
-Clinical factors: gastroenteritis, diarrhea
Absorption - Oral/GI - Additional Factors
- Intestinal SA - small gut: decreased SA: decreased absorption
- Diet
- Biliary function and pancreatic enzymes are underdeveloped which affects lipophilic drug solubility and absorption
Absorption - Oral/GI - Intestinal Metab/Enzymes
-Metabolizing enzymes and drug transporters re not well elucidated
EX: Gabapentin has decreased absorption in those under 5 years old from decreased L-amino transporter activity
EX: Decreased P-gp activity in neonates
Absorption - Transmucosal
- SL, nasal, rectal
- ~50% of rectal blood flow bypasses first pass metabolism
- Dose loss d/t expulsion
- Often convenient: Midazolam, APAP
Absorption - Skin
Neonates and infants have increased skin permeability due to:
-Increases in skin hydration
-Thinner stratum corneum
-Increased subcutaneous perfusion
-Increased BSA:Mass ratio
EX: Steroids (topical OTC hydrocortisone)
Absorption: IM
-Decreased muscle mass: decreased absorption tissue
-Poor muscle tone: decreased blood flow musculature
-More capillaries
-Evidence shows variable and decreases in absorption
EX: Antibiotics, phenobarbital
Advantages if slow absorption in preferred like with Vitamin K at birth
Distribution
- Vd is a ratio of total drug in body to the drug measured in the plasma
- Depends on hydrophilicity/lipophilicity, plasma protein binding, tissues binding of drug
- Drug disperses through body in compartments
- Understanding Vd helps guide loading doses by considering CL and affects on half lives
- Hydro/lipophilicity of drug determines which compartments it does in to
Distribution - Pediatric Compartment Size
- Changes relative to age
- Total body water (decreases with age) and body fat (increases with age) are examples
Total Body Water Changes
Preterm neonates: 85%
Term neonates: 75%
1 year old: down to 60%
Total Body Fat Changes
Preterm neonates: 2%
Neonates: 10-15%
1 year: 20-25%
Distribution - Plasma Protein Binding
- Neonates have decreases protein binding since there is less proteins, lower affinities, and more competing substrates like bilirubin and FFA
- Increases Vd, protein maturation occurs at about 10-12 months
Distribution Drug Examples (3)
- Gentamycin - hydrophilic, affects clearance and half life for neonates
- Phenytoin - free phenytoin is active, only 40-50% is bound in neonates compared to 80-90% in adults, decreases bilirubin and may end up with more free than bound phenytoin (Take free phenytoin levels)
- Ceftriaxone - displaces bilirubin, kernicterus risk, crosses BBB and can cause encephalopathy
Metabolism
- Phase I: structural changes, Phase II: conjugation (primarily in liver)
- Both phases involves enzymes or transporters
- Genetic polymorphisms can complicate things
Metabolism - Pediatric Enzymes
- each enzyme has unique ontogeny
- CYP3A7 = “neo” enzyme, active form in 0-6 months
- Others increase over time, though this isn’t linear
- Takes longer in preterm
- Reaches adult levels at about 2 years old
Metabolism - Phase II Enzymes in Peds
- UGTs have decreased activity - metabolize ~15% of medications (APAP, morphine for examples), matures at about 3 years old
- Acetyltransferase has decreased activity
- Sulfation is developed at birth, activity MAY be greater than adults
Elimination
- Driven by 3 kidney processes
- Eliminated from body in final detoxification process from kidney
- In pediatrics, immature CL increases the half life
Elimination - Ped. GFR
-Changes over months
-Only receive 5-6% of CO
-Increases after 34 week GA, increases CO and decreases vasculature resistance
-Doubles in first 1-2 weeks, then gradual increase until maturation at about 6 months
GFR, TE, and TA all mature at different rates
Considerations: Infectious disease, CAKUT, excipients
SCr Levels by Age
Neonates: 0.3-1
Infants: 0.2-0.4
Children: 0.3-0.7
Adolescents: 0.5-1
Schwartz Equation
-Used to estimate GFR in those 1-18 years old Original: K * L / SCr "Bedside" Schwarts: 0.413 * L / SCr -Use length, not age -Original equation overestimates GFR -EX: gentamycin
Elimination - TE/TA in Peds
- 20% of adult capacity at term
- Increases slowly over first year of life
- Multiple transporters are involved
Pediatric PD
- Different receptor sensitivity (numbers/affinities) at different ages
- Paradoxical effects: diphenhydramine (awaking effect in kids), antidepressants (depresses)
- Affect on growth and developments: tetracycline, corticosteroids, fluoroquinolones
Pregnancy Kinetics
- Material kinetics affected by pregnancys
- Absorption: decreased with N/V and increased gastric motility, decreased gastric acid changes bioavailability
- Distribution: increased total body fluid increases Vd, decreased albumin increases plasma concentrations, feta-placental compartment leads to drug accumulation and increased Vd
- Metabolism: Increased CO, increased hepatic flow, decreased CYP activity as gestation progresses, increased UGT
- Elimination: Increased GFR as gestation progresses which decreases half lives and plasma concentrations, tubular changes can also affect clearance (ex: digoxin)
Fetal Concerns
- Placental drug transporters = new field of study
- Synctiotrophoblasts: rate limiting step for transfer across placenta
- Brush border cell type increases microvilli drug gestation
- In utero drug exposure: inducing drugs change predictable profiles in drugs like Barbiturates, caffeine, glucocorticosteroids, tobacco
Pediatric Dosing
- No single method to determine appropriate dose
- Most are based on weight, but development isn’t linear and weight can rapidly change and have wide ranges
- Limitations to developing better models are blood requirements and allometric scaling not being effective for all drugs/age groups
- Alternatives in Population PK Modeling: avoid “vampirism,” more co-variants, limited knowledge on neonate enzyme ontogeny, need more clinical studies
Pediatrics - Vulnerable Population
- Development differences: PK/PD dynamics, dynamic weight, communication barriers
- Limited buffering capacity (electrolytes, anticoag.)
- Limited evidence to support safety and efficacy
- Lack of commercially available, pediatric-friendly dosage forms
Pediatric Dosage Forms
- Can’t swallow tablets and weight-based dosing is needed usually
- Want to minimize administration frequency, impact on lifestyle, and non-toxic excipients
- Want it to be convenient, reliable, easy, affordable, and stable
- ANSWER: solutions, suspensions, and dilutions
- *needs right concentration, standardized concentrations, accurate compounding, crushability (ISMP “Do Not Crush” List), palatability (when possible, sometimes a risk), bulk dispensing ideally**
