Developmental PK Flashcards
What are the different developmental stages?
preterm birth: 24-37 weeks of pregnancy
normal term birth: 40 +/- 2 weeks of pregnancy
perinatal stage: 29 weeks of pregnancy to 7 days after birth
neonate: birth to 28 days (1 month)
infant: 1 month to 2 years
child: 2 to 12 years
adolescent: 12 to 18 years
Why are pediatrics a special patient population?
growth and development
-heterogenous process
-maturation is a variable process
-pathological considerations
available PK/PD information
-clinical studies sue healthy adult subjects
-exclusion criteria
-therapeutic orphan
What are developmental milestones?
things we expect to see as the child develops
-babble, sit up, crawl, walk, talk, etc
remember there is variation in when these are seen
Describe typical body weight patterns as a child grows.
2 weeks after birth: 5-10% weight loss from birth weight
-neonates are born with lots of body water which is lost
4-6 months: infant should double birth weight
1-5 years: toddler gains about 2.2 kg
What occurs to body surface area to mass as a child ages?
body surface area to mass decreases
-they are gaining weight
Do we use the proposed formulas for empiric pediatric dosing?
probably would never use them
-likely not great estimations
What is developmental pharmacology?
PK and PD of drugs and the clinical characteristics of neonatal and pediatric populations
how human growth and development change PK/PD relationship in unique patient
What are the two goals of developmental pharmacology?
understand the impact of maturation on drugs ADME (PK)
describe the PD: knowing the concentration of drugs and expected response
What is the effect of aging on pharmacokinetics?
as children age, there are pharmacokinetic changes
-anatomic and physiological changes
-age-related changes in organ function are responsible for changes in PK (kidney, liver)
When is the rate of maturation of ADME processes the greatest?
in the first 2 years of life
-slower in neonatal period, increasing into childhood
How are rate and extent of GIT absorption influenced by aging?
they are influenced by developmental maturation
-GIT surface area
-GIT perfusion
-gastric pH
-gastric emptying and intestinal motility
-pancreatic exocrine and biliary function
-bile salts
-enzyme activity and 1st pass effects
What does gastric pH influence?
drug stability
dissolution
ionization
How does gastric pH change over time after birth?
birth: neutral gastric pH
progressive decrease over several weeks to years
What does gastric emptying & intestinal motility influence?
affect intestinal drug absorption
What is the effect of age on gastric emptying?
limited understanding of the effect of age
-changes in Tmax in younger ages (?delayed onset)
comparable to adult values and function by 2 years
How can food impact absorption?
binding interactions
What are the major factors governing distribution?
- body composition (total body water, adipose tissue)
- plasma protein binding and tissue binding (affinity and capacity)
- hemodynamic factors (tissue perfusion and CO)
What does Vd influence?
the loading dose
-hence, larger Vd relative to body weight will require larger mg per kg doses
What is the relationship between total body water and lipophilic tissue in the early years?
body water composition starts high and trends down, reverse for lipophilic tissue
-preterm neonate BW: 80-90%
-term neonate BW: 70%
-1-2 yrs BW: 60%
-greater than 2 yrs BW: stabilization
Why does the high total body water of neonates matter in regards to drugs?
think of a drug that has a low Vd ( < 1 L/kg)
neonate: large water container
-dilutional –> higher doses of drug likely required to produce therapeutic effect
-unpredictable
How does protein binding change in early years?
lower concentration of plasma binding proteins
-albumin, alpha-1 acid glycoprotein, plasma globulins
binding affinity changes
presence of pathophysiologic conditions or endogenous cpds (bilirubin, FFA)
Why does protein binding matter?
free fraction of drug exerts pharmacological effect
increased free drug = affect pharmacological effect and clearance
highly bound drugs and narrow therapeutic index (ex: digoxin)
How can disease impact distribution?
obesity: increased lipid compartment
malnutrition: albumin deficiency
sepsis: plasma compartment
How does hepatic blood flow change as the child matures?
at birth: hepatic blood flow and oxygen tension rapidly change
-umbilical vein blood supply terminated
-portal venous and hepatic arterial blood increase with closure of the patent ductus venosus
How does hepatic blood flow changes impact elimination in neonates?
unlikely to affect elimination capacity in neonates
How does splanchnic blood flow change early in life?
increases rapidly postnatally to support mucosal growth and enteral nutrition
How does renal blood flow change early in life?
renal perfusion at birth < 20% renal perfusion of adults
as child ages CO increases and renal vascular resistance decreases = increased GFR
What does elimination capacity depend on?
developmental changes in:
-function
-relative size
How does organ/body mass compare between infants & neonates to adults?
higher ration of organ/body mass in neonates and infants
-enhanced ability to eliminate drug
age-dependent Cls may reflect liver size/body weight differences (not Clint/g liver)
How does enzyme maturation rate differ early in life?
slower in infancy and then ramps up in adolescence and adulthood
influences DDIs (relevant in infants?)
Describe general patterns of hepatic enzyme ontogeny.
developmental switches: changes in predominant metabolic pathway with maturation
-ex: CYP3A7 (neonates) vs CYP3A4 (adults)
-alteration in metabolite profiles, toxicity risk, efficiency of elimination
variation in enzymes
-vary in number through developmental stages
-may be different between children of the same age
What is the GFR of a full-term newborn?
10-20 ml/min/m2
-rapid increase during the first weeks of life –> adult values by 3-5 months
Which aspect of renal elimination develops slower in infants?
tubular secretion and reabsorption
Describe the developmental changes in kidney anatomy.
nephrogenesis complete at 36 weeks
-thereafter, increases in renal mass due to increase in renal tubular growth
children have the fastest rate of increasing glomerular and tubular cell size
What happens to GFR in premature infants?
reduced GFR
-slower pattern of GFR development in the first 1-2 weeks PNA
When does GFR approach adult levels?
by 6 months of age
When does GFR exceed adult levels?
early childhood to early adolescence
-maximum relative kidney weight
What is the impact of immature renal tubules?
compromises passive and active reabsorption and excretion processes
-20-30% adult value at birth
-increases slowly and variably
When does renal tubular elimination reach adult values?
1-5 years of age
What is the impact of transporters on renal tubular elimination in pediatrics?
little information
