lec 20 - pediatric PK (robinson)

challenges children pose

• 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

• limited capacity to buffer errors

  • more limited internal reserves than adults

terminology

• gestational age

  • 1st day of mom’s last menstrual cycle → birth

• chronological or post natal age

  • birth → present

• post-menstrual age

  • gestational age + chronological age

• neonate

  • birth to 1 month

  • pre-mature = <37 weeks

  • full term = 37-42 weeks

• infant

  • 1 month - 1 year

• child

  • 1-12 years

• adolescent

  • 13-18 years

example of age

baby born at 28 weeks gestation is now 21 days old

gestational age?

full mature or preemie?

post-menstrual age?

neonate, infant or child?

• gestational age = 28 weeks

• preemie

• post-menstrual age = 28 weeks + 21 days = 31 weeks

• neonate

gastric absorption

gastric emptying and intestinal motility

• most drug absorption takes place in the duodenum

• gastric emptying

  • significantly delayed in neonates/infants (6-8 hours)

  • adult values (20-50 minutes) by 6-8 months

• intestinal motility

  • prolonged and irregular peristalsis

  • infantile diarrhea (shortens transit time)

• delayed and possibly enhanced absorption

gastric mucosal integrity

• neonates at higher risk of intestinal damage

  • due to poor oxygenation

• subject to intestinal injury and necrotizing enterocolitis (NEC) from hypertonic solutions

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

• minimize osmolality load

minimizing osmolality load

• american academy of pediatrics recommends formulas not exceed 450 mOsm/kg

• what about medications?

  • poly-vi-sol: 10,853 mOsm/kg

  • acetaminophen suspension: 5,017 mOsm/kg

  • ferrous sulfate: 3,117 mOsm/kg

  • calcium glubionate syrup: 2,034 mOsm/kg

  • calcium gluconate injection: 302 mOsm/kg

percutaneous absorption

• immature epidermal barrier in premature neonates

  • mature stratum corneum in full-term neonates

• increase skin hydration and increased BSA:weight

• increased absorption up to 6 years (vs adults)

• inadvertent poisoning

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

intramuscular absorption

• variable and unpredictable in premature neonates and newborns

  • decreased muscle mass

  • insufficient muscle tone and contraction

  • decreased blood flow

• painful

• AVOID IM injection whenever possible

distribution: Vd:body composition

Vd:body composition

• total body water

  • infant > younger children > adults

    • premature (85%) > full term (70%)

  • larger V_d for water-soluble drugs

• total body fat

  • infants < adults

    • premature (1%) < full term (15%)

  • smaller V_d for lipophilic drugs

• in general

  • larger doses (mg/kg) of water soluble drugs

    • neonates have higher total body water percentage so Vd is larger b/c drug distributes into that extra body water so to achieve same plasma concentration you need higher dose

  • smaller doses (mg/kg) of lipophilic drugs

    • neonates have less body fat so lipophilic drugs have less tissue to distribute into so Vd is smaller → smaller doses needed to avoid high plasma concentrations

Vd examples

• aminoglycosides = water soluble so more absorption in neonates and less in adults

• benzodiazepines = lipophilic so more absorption in adults vs neonates

distribution: protein binding

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

• highly protein bound drugs may have higher free fraction in neonates

• avoid drugs known to compete for albumin sites in the neonatal period

  • this is bc plasma protein binding is so weak to begin with if you introduce a competitor theres going to be like no plasma protein binding which is BAD

protein binding example

• phenytoin

  • ~90% protein bound in adults

  • ~80% protein bound in neonates

• therapeutic range

  • adults: 10-20 mcg/mL

  • neonate: 6-15 mcg/mL

  • therapeutic free level: 1-2 mcg/mL

metabolism: phase I rxns

• oxidation, reduction, hydrolysis

• total quantities of P450 enzymes

  • neonates < adults

• maturation correlates with postnatal age

  • adult values by 6 months

  • p450 subfamilies mature at different rates

• metabolizing capacity

  • older infants and children (peaks at 2-3 years) >> adults

• different pathways
  

age related phenytoin dosing

• increases then decreases b/c neonates have less metabolizing capacity than adults but then…

• peak at 6 mo to 3 year b/c thats when metabolizing capacity is the greatest and then starts decreasing

metabolism: phase II reactions

• glucuronidation

  • limited during the neonatal period

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

• sulfation

  • well developed at birth

  • may compensate for limited glucuronidation

metabolism

recommended dosing schedules in children are based on population based estimates of CL; careful monitoring of pediatric dosing, serum concentrations and potential toxicity should be emphasized

excretion

• glomerular filtration

  • matures quickly after birth

  • adult values by 6-12 months

• tubular functions

  • maturation proceeds more slowly

  • adult levels by 6-8 months; up to 2 years

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

creatinine clearance

modified schwartz/schwartz equation

• may NOT provide an accurate estimation of creatinine clearance for infants < 6 months of age or for pts with severe starving or muscle wasting

special considerations in children

• age specific dosing regiments

• drug delivery

• blood sampling

• interpretation of drug levels

age specific dosing regimens

NO standard dosing for peds

pediatric references

• pediatric and neonatal dosage (lexicomp)

• neofax (micromedex)

• teddy bear book

• more

• rutgers resources

  • pediatric and neonatal→ lexicomp

  • neofax → microedex

  • red book (AAP) → STAT!ref

which dose to choose?

• dosing ranges

  • age

  • diagnosis

    • meningitis vs UTI

  • concurrent disease states

    • cancer, gastroenteritis

  • organ function

    • renal or hepatic disease

what to be careful about

• units

  • mg/kg/dose times desired frequency

    • acetaminophen 15 mg/kg/dose q4h prn

  • mg/kg/day divided by the desired frequency

    • ampicillin 200 mg/kg/day divided q8h

  • mg/m²/day

    • acyclovir 500 mg/m²/dose q8h

  • in general when a patient’s calculated dose exceeds the adult dose, the pt should be dosed according to adult medication guidelines

  • KNOW WHEN TO SAY WHEN

drug delivery

• dosage form

• route of admin

• delivery system

• method of admin

drug delivery: oral admin

• give orally whenever possible

• solid vs liquid

  • depends on age and developmental level

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

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

• chewable tabs preferred when feasible

• beware of preservatives

modify commercial products

• dilute liquids with an appropriate diluent to achieve desired concentration

• split tablets

  • if the patient’s dose is a measurable fraction

• injectable drugs may 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

  • use references, if available

  • do NOT crush sustained release products

  • watch for medication/enteral nutrition interactions

drug delivery: IV delivery

• ensure accurate prep and admin

  • choice of syringe and needle size

  • frequently small volumes

    • delayed drug delivery or underdosing may occur

    • FLUSH lines with adequate but min. volume

    • pediatric patients are susceptible to fluid overload

      • volumes of IV solutions need to be kept ta min

    • IV delivery system

      • syringe pumps with microbore IV tubing preferred

      • volumetric control devices

        • beware of dead space (up to 30 mL in standard IV tubing)

case study

baby boy brown is 35 week GA neonate being treated with ampicillin and gentamicin for sepsis. his nurse draws the gentamicin peak and trough levels around his 4/14 1300 dose (dose #3)

peak: 2.1 mcg/mL (drawn at 4/14 1400)

trough: 1.8 mcg/mL (drawn at 4/14 1230)

• timings of the peak blood draw was incorrect

• trough should be drawn right before next dose. about 30 minutes → so 1230 which is correct

• peak should be drawn 30 minutes to 1 hour after the end of infusion

  • with this drug 30 minutes admin and 30 mins flush so anther 30 minutes after flush is when it should be measured so it should be 1430

syringe pump with microbore tubing

blood sampling

• assess need to draw drug levels

  • NOT always necessary (empiric treatments - starting treatment on the most likely conditions before lab confirmation)

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

  • ongoing maturation of renal and hepatic function

  • rapidly changing physiological status

    • weight and body compartments

• minimize number of blood samples

• obtain the minimal amount of blood when sampling

• timing is everything

  • steady state, other labs, quality of life

to draw or not to draw:
mary is a 10 year old girl admitted with fever and neutropenia. she is started on cefepime and tobramycin. she is clinically stable and does NOT have any obvious sources of infection on physical exam. renal function is normal.

do we need to order tobramycin levels at this time?

probably not b/c short empiric use; stable renal function; no signs of toxicity

to draw or not to draw:

mary grows pseudomonas aeruginosa from her peripheral and central blood cultures. she is hemodynamically stable. ID recommends continuing cefepime and tobramycin for 14 days. she has received 3 doses of tobramycin to date (4/14 0400, 4/14 1200, 4/14 2000). next dose is 4/15 0400.

if and when should we draw tobramycin levels

yes we should draw b/c prolonged therapy

draw 4/15 0330 for trough and 1230 for peak

factors that are important when interpreting levels

• exact time of sampling

• exact time of all relevant dosing

• administration and sampling method

• dosing regimen

  • dose, frequency, duration, dosage form, route

• patient characteristics

  • age, weight, diagnoses, organ function

• concurrent medications

• indication for medication and level

• therapeutic range