pediatric PK Dr. Robinson

Abraham Jacobi

- Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but...has its own independent range and horizon

challenges that children pose

- weight-based dosing

- necessity for alterations

- absent/limited communication skills

- limited capacity for buffer errors

weight-based dosing

- involves more calculations than for adults

necessity for alterations

- commercially available products are adult focused

absent/limited communication skills

- young children do not have communication skills to warn about potential errors or adverse effects

- reliant on family members for the info, so it leads to more potential for error

limited capacity to buffer errors

- more limited internal reserves than adults

gestational age

- first day of mom's last menstrual cycle to birth

chronological [or postnatal] age

- birth to present

postmenstrual age

- gestational age + chronological age

neonate

- birth to 1 month

premature:

<37 weeks

full term:

- 37-42 weeks

infant

- 1 month to 1 year

child

- 1 to 12 years

adolescent

- 13 to 18 years

Gastric emptying alterations in pediatrics

- significantly delayed in neonates/infants [6-8 hours]

- adult values [20-50 minutes] by 6 to 8 months

intestinal motility alterations in pediatrics

- prolonged and irregular peristalsis

- infantile diarrhea shortens transit time

- delayed and possible enhanced[not clinically significant] absorption

gastric mucosal integrity

- neonates at higher risk of intestinal damage due to poor oxygenation

- subject to intestinal injury and necrotizing enterocolitis [NEC]

necrotizing enterocolitis [NEC]

- from hypertonic solutions

- hypo perfused dead gut; basically liquified intestines

- life-threatening

how to avoid NEC

- avoid high osmolality drugs and oral drugs until full enteral feeding

- minimize osmolality load

- ex: using IV meds orally; sodium replacements; dilution between or after feeds

minimizing osmolality load

- the number to remember is 450 mOsm/kg

- kg represents solute volume and not the patient weight

- in general salt should not exceed this number

percutaneous absorption

- immature epidermal barrier in premature neonates [almost transparent]

- mature stratum corneum in full-term neonates

- increased skin hydration

- increased BSA: weight

- increased skin absorption up to 6 years [vs adults]

the toxicities of percutaneous absorption in children

- inadvertent poisoning

- use caution in application of any topical agents in young patients, especially premature neonates in the first 2-3 weeks of life

- ex: neonatal spongioform myelinopathy after babies were bathed in hexachlorophane skin disinfectant

intramuscular absorption

- variable and unpredictable in premature neonates and newborns

- decreased muscle mass

- insufficient muscle tone and contractions

- decreased blood flow

- painful

- overall, AVOID IM injection whenever possible

Total body water

- infant > younger children > adults

- premature [85%] > full term [70%]

Vd for water soluble drugs in babies

- larger

total body fat

- infants < adults

- premature [1%] < full term [15%]

Vd for lipophilic drugs in babies

- smaller

hydrophilic example: aminoglycosides (gentamicin)

- larger Vd in neonate compared to adult

lipophilic example: benzodiazepines (lorazepam)

- smaller Vd in neonate compared to adult

main point of Vd in pediatrics

- larger doses [mg/kg] of water-soluble drugs

- smaller doses [mg/kg] of lipophilic drugs

protein binding

- decreased plasma protein binding in neonates and infants

- decreased affinity and binding capacity of albumin binding sites

- risk of displacing bilirubin from albumin

risk of displacing bilirubin from albumin

- if bilirubin is free, is can cross BB and cause Kernicterus [brain damage]

highly protein bound drugs in neonates

- may have higher free fraction

what to avoid regarding protein binding for neonates

- drugs known to compete for albumin sites

- ex: sulfa drugs, ceftriaxone

protein binding example: phenytoin

- 90% protein bound in adults [10% free]

- 80% protein bound in neonates [20% free]

phenytoin therapeutic range

- 10-20 mcg/mL

- neonate: [6-15 mcg/mL]

- therapeutic free level: 1-2 mcg/mL

Phase 1 reactions

- oxidation, reduction, hydrolysis

- total quantities of P450 enzymes less in neonates compared to adults

- maturation correlates with postnatal age

- different pathways are taken compared to adults

maturation of P450 family

- adult values by 6 months

- P450 subfamilies mature at different rates

metabolizing capacity

- older infants and children [peak at 2-3 years] >> adults

why different metabolism pathways?

- maturity timeline of different metabolism pathways and families

Phase II reactions

- glucuronidation and sulfation

glucuronidation

- limited during the neonatal period

- adult values by 18 to 24 months; up to 48 months

sulfation

- well developed at birth

- may compensate for limited glucuronidation

- ex: acetaminophen can be used

overall message regarding metabolism in neonates, infants, and children

- recommended dosing schedules in children are based on population-based estimates of clearance

- careful monitoring of pediatric dosing, serum concentrations, and potential toxicity should be emphasized

excretion

- Glomerular filtration and tubular functions

- lower doses of renally cleared drugs during the 1st week of life, then increases with age

glomerular filtration

- matures quickly after birth

- within the first month, you see more blood flow and increased GFR as a result

- adult values by 6 to 12 months

tubular functions

- slow maturation

- adult levels by 6 to 8 months, up to 2 years

modified schwartz equation (IDMS-traceable method)

- CrCl [mL/min/1.73 m^2] = 0.413 * height [cm]/ Scr [mg/dL]

- no weight! you need accurate height and Scr

- may no provide an accurate estimation of creatinine clearance for infants < 6 months of age or for patients with severe starving or muscle wasting

- Schwartz equation

- CrCl [mL/min/1.73 m^2] = k* height [cm]/ Scr [mg/dL]

- k is age-based compared to the modified one

special considerations in children

- age-specific dosing regimens

- drug delivery

- blood sampling

- interpretation of drug levels

age-specific dosing regimens

- no standard dosing in pediatric patients

pediatric references (good ones)

- Pediatric and Neonatal dosage handbook [Lexidrug]; rutgers

- Neofax [Micromedex]; rutgers

- Teddy Bear Book, Pediatric injectable drugs

- Pediatric drug formulations for extemporaneous formulations

- Red Book [AAP] on infectious diseases and antibiotic disease; organized by organism; rutgers

pediatric references (bad ones)

- Facts and Comparisons

- AHFS Drug information

- Harriet-Lane Handbook [pediatric house officers' manual]

what are dosing ranges based on

- age

- diagnosis [meningitis vs UTI]

- concurrent disease states [cancer, gastroenteritis]

- organ function [renal or hepatic disease]; Neofax doesn't have this

what to be careful of when talking about dosing with colleagues

- units!

- in general, when a patient's calculated dose exceeds the adult dose, the patient should be dose according to adult medication guidelines

different units in pediatric weight based dosing

- mg/kg/dose times a desired frequency

- mg/kg/day divided by desired frequency

- mg/m^2/day, which requires a BSA calculation using height and weight

drug delivery components

- dosage form

- route of administration

- delivery system

- method of administration

oral administration

- give orally whenever possible

- solid vs liquid

- chewable tablets preferred when feasible

- beware of preservatives, especially when stacking medications

solid vs liquid

- depends on age and developmental level

- most children can safely swallow solid forms of medications by 5-6 years

- younger children may be at risk of aspirating solid dosage forms

modifying commercial products

- dilute liquids with an appropriate diluent to achieve the desired concentration

- splitting tablets if the patient's dose is a measurable fraction

- injectable drugs may need to be used as oral dosage forms if oral bioavailability data exists

- crush tablets or empty capsules and mix with beverages, soft foods, or enteral feeding formulas or extemporaneously prepare oral liquid

what to watch out for when modifying commercial products

- use references if available

- do not crush sustained release products

- watch for medication/enteral nutrition interactions

- sometimes you could dilute bedside and immediately administer if needed

IV delivery

- choice of syringe and needle size

- frequently small volumes

small volumes in IV delivery

- delayed drug delivery or underdosing may occur

- FLUSH lines with adequate, but minimal volume

- pediatric patients are susceptible to fluid overload, so volumes of IV solutions need to kept at a minimum

IV delivery system

- syringe pumps with microbore IV tubing preferred

- volumetric control devices have dead space of up to 30 mL in standard IV tubing

- important to flush line and then take peaks 30 minutes later for accurate sampling and data

accurate prep for IV delivery

- a syringe can measure at least 10-20% of total volume of device, so anything less may be inaccurate

- ex: 1 mL syringe can do 0.1-0.2 mL accurately, but not 0.05 mL

assess need to draw drug levels

- not always necessary [empiric treatments]

- subtle signs of toxicity or lack of effect difficult to assess

- ongoing maturation of renal and hepatic function

- rapidly changing physiological status in weight and body compartments

general points for blood sampling in pediatrics

- minimize number of blood samples

- obtain the minimal amount of blood when sampling

- timing is everything, so make sure patient at steady state, take blood when there are other labs, and ensure quality of life

interpretation of levels

- exact time of sampling

- exact time of all relevant doses

- administration and sampling method

- dosing regimen

- patient characteristics

- concurrent medications

- indication for medication and level

- therapeutic range [population based NOT individual]

what are you treating?

- TREAT THE PATIENT NOT THE LEVEL