Developmental PK

Question 1

What are the different developmental stages?

Answer 1

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

Question 2

Why are pediatrics a special patient population?

Answer 2

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

Question 3

What are developmental milestones?

Answer 3

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

Question 4

Describe typical body weight patterns as a child grows.

Answer 4

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

Question 5

What occurs to body surface area to mass as a child ages?

Answer 5

body surface area to mass decreases
-they are gaining weight

Question 6

Do we use the proposed formulas for empiric pediatric dosing?

Answer 6

probably would never use them
-likely not great estimations

Question 7

What is developmental pharmacology?

Answer 7

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

Question 8

What are the two goals of developmental pharmacology?

Answer 8

understand the impact of maturation on drugs ADME (PK)
describe the PD: knowing the concentration of drugs and expected response

Question 9

What is the effect of aging on pharmacokinetics?

Answer 9

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)

Question 10

When is the rate of maturation of ADME processes the greatest?

Answer 10

in the first 2 years of life
-slower in neonatal period, increasing into childhood

Question 11

How are rate and extent of GIT absorption influenced by aging?

Answer 11

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

Question 12

What does gastric pH influence?

Answer 12

drug stability
dissolution
ionization

Question 13

How does gastric pH change over time after birth?

Answer 13

birth: neutral gastric pH
progressive decrease over several weeks to years

Question 14

What does gastric emptying & intestinal motility influence?

Answer 14

affect intestinal drug absorption

Question 15

What is the effect of age on gastric emptying?

Answer 15

limited understanding of the effect of age
-changes in Tmax in younger ages (?delayed onset)
comparable to adult values and function by 2 years

Question 16

How can food impact absorption?

Answer 16

binding interactions

Question 17

What are the major factors governing distribution?

Answer 17

1. body composition (total body water, adipose tissue)
2. plasma protein binding and tissue binding (affinity and capacity)
3. hemodynamic factors (tissue perfusion and CO)

Question 18

What does Vd influence?

Answer 18

the loading dose
-hence, larger Vd relative to body weight will require larger mg per kg doses

Question 19

What is the relationship between total body water and lipophilic tissue in the early years?

Answer 19

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

Question 20

Why does the high total body water of neonates matter in regards to drugs?

Answer 20

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

Question 21

How does protein binding change in early years?

Answer 21

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)

Question 22

Why does protein binding matter?

Answer 22

free fraction of drug exerts pharmacological effect
increased free drug = affect pharmacological effect and clearance
highly bound drugs and narrow therapeutic index (ex: digoxin)

Question 23

How can disease impact distribution?

Answer 23

obesity: increased lipid compartment
malnutrition: albumin deficiency
sepsis: plasma compartment

Question 24

How does hepatic blood flow change as the child matures?

Answer 24

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

Question 25

How does hepatic blood changes impact elimination in neonates?

Answer 25

unlikely to affect elimination capacity in neonates

Question 26

How does splanchnic blood flow change early in life?

Answer 26

increases rapidly postnatally to support mucosal growth and enteral nutrition

Question 27

How does renal blood flow change early in life?

Answer 27

renal perfusion at birth < 20% renal perfusion of adults
as child ages CO increases and renal vascular resistance decreases = increased GFR

Question 28

What does elimination capacity depend on?

Answer 28

developmental changes in:
-function
-relative size

Question 29

How does organ/body mass compare between infants & neonates to adults?

Answer 29

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)

Question 30

How does enzyme maturation rate differ early in life?

Answer 30

slower in infancy and then ramps up in adolescence and adulthood
influences DDIs (relevant in infants?)

Question 31

Describe general patterns of hepatic enzyme ontogeny.

Answer 31

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

Question 32

What is the GFR of a full-term newborn?

Answer 32

10-20 ml/min/m2
-rapid increase during the first weeks of life –> adult values by 3-5 months

Question 33

Which aspect of renal elimination develops slower in infants?

Answer 33

tubular secretion and reabsorption

Question 34

Describe the developmental changes in kidney anatomy.

Answer 34

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

Question 35

What happens to GFR in premature infants?

Answer 35

reduced GFR
-slower pattern of GFR development in the first 1-2 weeks PNA

Question 36

When does GFR approach adult levels?

Answer 36

by 6 months of age

Question 37

When does GFR exceed adult levels?

Answer 37

early childhood to early adolescence
-maximum relative kidney weight

Question 38

What is the impact of immature renal tubules?

Answer 38

compromises passive and active reabsorption and excretion processes
-20-30% adult value at birth
-increases slowly and variably

Question 39

When does renal tubular elimination reach adult values?

Answer 39

1-5 years of age

Question 40

What is the impact of transporters on renal tubular elimination in pediatrics?

Answer 40

little information