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Age-Kinetics-2006-1

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Age and Pharmacokinetics
Pediatric and Geriatric Considerations
M. E. Blair Holbein, Ph.D.
Clinical Pharmacologist
Presbyterian Hospital of Dallas
Pediatric Pharmacology - History

Some of the most disastrous therapeutic misadventures
occurred in pediatrics.



Thalidomide 1957
Chloramphenicol 1959
Directly led to the “modern era” of pharmaceutical
regulation with Kefauver-Harris Drug Amendments of
1962

Requirement for demonstrated efficacy and safety for FDA
approval and USA marketing.
Pediatric pharmacology - What’s unique?

Continuous development from embryo to adolescent




“Perpetual pharmacologic moving target”
Pharmacodynamics and pharmacokinetics change with time
The most profound differences occur in the first weeks
through first year of life.
Descriptive pharmacology (especially for new drugs) in
pediatric patients is often lacking




Children are not “miniature adults”
• Dosing based on “rule” (Young’s, Clark’s) or scaling (by body
weight or body surface area) not always predictable for a
given drug.
Animal studies not always predictive.
Clinical studies in children fraught with ethical and financial
hurdles.
Administration of drug can also be problematic.
Pediatric pharmacology - Approved drugs



Children are “therapeutic orphans”
Only 20-30% of approved drugs have pediatric labeling
FDA has encouraged pediatric studies
• Financial incentive to conduct studies
• Orphan and off-patent drugs - no incentive to do studies
• Increased studies resulted in new labeling for 40 drugs.
• For approval of selective number of new drugs pediatric
studies have been required.

Resources


Center for Drug Evaluation and Research at FDA www.fda.gov/cder/pediatric/
Pediatric Drug Labeling: Improving the Safety and Efficacy of
Pediatric Therapies. JAMA. 2003;290:905-911.
The “Moving Target” - Developmental Changes



Body composition
Organ function
Drug metabolizing enzymes





Unique metabolic pathways
Renal function
Receptor response
Unique disorders
Extremely small margin of error for the most fragile
patients


Errors can be devastating
Individual variance unpredictable
Developmental Changes in Physiologic Factors That Influence Drug Disposition in
Infants, Children, and Adolescents
Kearns, G. L. et al. N Engl J Med 2003;349:1157-1167
Developmental Pharmacology - Absorption - GI

Gastric acid - approaches adult values ~ 3 mo in fullterm infants.



Bioavailability increased for acid-labile drugs (some penicillin
derivatives)
Decreased for drugs requiring acid to be absorbed.
Digestive enzymes including pancreatic enzymes are
low in newborns.

Colonization of the gut occurs rapidly after birth but is highly
variable and unpredictable.
Developmental Pharmacology - Absorption - GI

Gastric emptying


GI motility




Delayed and unpredictable in newborns - adult values ~ 6 mo.
Slow in newborns; may be increased in children.
Usually affects the rate but not the fraction of drug absorbed.
The absorptive surface area/BSA is > infants and children vs.
adults
The impact on absorption is usually minimal but is
unpredictable
Developmental Pharmacology - Absorption - Skin

Percutanous absorption




Premature infant has a significantly less effective skin
barrier to absorption of drugs and toxins


Directly related to the degree of skin hydration.
Inversely related to the thickness of the stratum corneum.
• Thinnest in premature neonate
Greater extent of cutaneous perfusion
Ex. Hexachlorophene toxic to immature infants
Newborn skin surface area : body weight is 3X > adult
Other Routes of Drug Administration

Intramuscular





Rectal




Lipid solubility favors distribution from site into circulation (rate)
Water soluble at physiologic pH to prevent precipitation
Highly susceptible to variance in absorption due to blood flow
and relative muscle mass
• Dispersion driven by muscle contraction (low in neonates and
immobility)
• Reduced skeletal-muscle blood flow in neonate
Can be extremely painful, cause hemorrhage, nerve damage,
abscess, necrosis, fibrosis, and  CPK
Absorption is excellent for some agents
Less first pass effect due to decreased hepatic clearance
Pulmonary for site specific agents
Unintentional


Breast milk
Transplacental
Developmental Pharmacology - Absorption
PK
Pathway
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
3–5 mo.
Late infanttoddler
6 – 24 mo.
Older child
, 
, 




Dermal






Lung






Absorption
Oral
Developmental Pharmacology - Distribution


Larger extracellular and total-body water spaces in
neonate and young infants
Adipose stores also have higher ratio of water to lipid


Plasma proteins



RESULT: Lower plasma levels (relative to weight) for water
soluble drugs. Effect on lipid soluble less
Low in premies and neonates ( free fraction)
Most important in displacement of bilirubin from albumin
resulting in toxicity (kernicterus)
Tissue transporters - P-glycoprotein ATP-binding
cassette family of transporters


May limit cellular uptake of xenobiotic substrates [blood-brain
barrier, hepatocytes, renal tubular cells and enterocytes]
Very limited data; premature infants probably most affected
Developmental Pharmacology - Distribution Sites
Developmental Changes in Distribution Sites
% Total Body Weight
100
Total Body Water
Extracellular Water
Body fat
80
60
40
20
0
0
3 mo.
6 mo.
9 mo.
1 yr
Age
5 yr
10 yr
20 yr
40 yr
Developmental Pharmacology - Metabolism

Prior to birth the fetus is in a relatively protected
environment



Maturation of drug metabolizing enzymes occurs
longitudinally



The xenobiotic clearing processes of the mother prevent
exposure of the fetus.
The placenta also acts as a barrier.
The very young have very low activity
• Ex. Cardiovascular collapse in chloramphenicol associated
“gray baby syndrome”
Cause for caution for drugs that have wider therapeutic index in
adults
• Ex. Methylxanthines, nafcillin, 3rd generation cephalosporins,
captopril and morphine
Distinct patterns for each class and isoform of drug
metabolizing enzymes.
Development of Drug-Metabolizing
Enzymes - Phases of Drug Metabolism

Phase I



Oxidation
Reduction
Hydrolysis

Phase II

Conjugation
Development of Drug-Metabolizing Enzymes Phase I - Oxidation/Reduction/Hydrolysis

Predominant isoform (liver) CYP3A7 in prenatal period



Peaks at birth, then declines rapidly to undetectable in adults
Role to detoxify dehydroepiandrosterone sulfate, teratogenic
derivatives of retinoic acid
Within hours after birth other isoforms begin to appear.



Each has individual pattern of development.
Most are at or above adult levels by 1 year.
Examples
•
•
•
•
Midazolam clearance changes 7X in 3 months (1.2  9 ml/min)
Phenytoin T 1/2 in premies 75  20 hr in 1 wk old full term infant
Carbamzepine clearance children > adults
Methylxanthine demethylation exceeds adults by 4 months (and
declines in puberty in sex-based divergence)
Development of Drug-Metabolizing Enzymes Phase II - Conjugation Reactions


Ontogeny less well characterized than Phase I reactions
Glucouronosyltransferase (glucuronidation) is decreased
in newborns and young children compared to
adolescents and adults




Present by 24 wk gestational age
Morphine glucuronidation correlates with post-conceptional age
Morphine conjugate more potent (premies require increased
dose for equivalent analgesia)
Clearance of most agents more efficient in prepubescent
children than adults (relative to bodyweight)
JPET Vol. 300, Issue 2, 355-360, February 2002 The Ontogeny of Human Drug-Metabolizing Enzymes: Phase I Oxidative Enzymes
Relative Half-lives of CYP1A2 Substrates
Ginsberg et al. Pediatrics 2004; 113: 973.
Relative Half-lives of CYP3A Substrates
PEDIATRICS Vol. 113 No. 4 April 2004, pp. 973-983
Developmental Pharmacology -Metabolism:
Phase I
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
3–5 mo.
Late infanttoddler
6 – 24
mo.
CYP1A2




 Scale BW3/4
 Scale BW3/4
CYP2E1




 Scale BW3/4
 Scale BW3/4
CYP A




 Scale BW3/4
 Scale BW3/4
CYP3A7






Other CYPs




 Scale BW3/4
 Scale BW3/4
ADH




 Scale BW3/4
 Scale BW3/4
PK Pathway
Metabolism:
Phase I
Older child
Developmental Pharmacology - Metabolism:
Phase II
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
3–5 mo.
Late infanttoddler
6 – 24
mo.
Glucuonidation






N-acetylation






PK Pathway
Metabolism:
Phase Ii
Older child
Developmental Pharmacology - Renal Elimination

Maturation of renal function dynamic



Begins with fetal organogenesis (9 wk gestational age)
Complete by early childhood
GFR correlates with nephrogenesis and postnatal renal
and intrarenal bloodflow.
Acquisition of Renal Function
160
140
GFR/Rel PAH Cl ro GFR
120
100
80
60
Glomerular
Filtration Rate
PAH Clearance
40
20
0
1-2
days
2-4 wk
2 mo
6 mo
1 yr
Age
2 yr
6 yr
12 yr
Developmental Pharmacology - Renal Elimination

Therapeutic implications


Estimation of renal function necessary for determining dose
regimen for drugs with extensive renal clearance
• Ex. Ceftazidime, famotidine, aminoglycosides.
• Measurement of drug levels often necessary
Some drugs also alter renal maturation or renal blood
flow.

Ex betamethsone, indomethacin
Developmental Pharmacology Pharmacodynamics


Very little data; most accepted practices are based on
observation
Anecdotal evidence for altered response to




Warfarin
Cyclosporine
Midazolam
Erythromycin (intestinal motilin receptors)
Criteria for Using a Drug in a Child or Infant

Has there been documented efficacy for the medication
for the disorder in newborn or older infants/children.


Is the data from adequate clinical trials (randomized, controlled,
size, power, similar age/maturity)?
Has the safety been established for pediatric
population?
Criteria for Using a Drug in a Child or Infant




Has the pathway of drug clearance been established in
children/infants?
Is that pathway established in the child/infant you are
treating (based on maturity or physical state)?
Is there reason to believe that pathway may be
compromised in the specific child/infant (genetics,
disease state, concomitant therapy)?
Have the pharmacokinetics been established in similarly
aged children?
Criteria for Using a Drug in a Child or Infant






Is there a safe route to administer the drug? (intact GI
tract, central access, intact skin, nontoxic solvent)
Is displacement an issue for albumin binding or bilirubin
displacement?
Are there technical issues surrounding administration,
e.g. solvents, preservatives, volume?
Is there an established dose and interval appropriate for
age and disease state of the child?
Have a plan for monitoring for appropriate response to
the agent.
Look for adverse effects of the agent.
Criteria for Using a Drug in a Child or Infant

The very small doses required in the most immature
patients and the immature clearance pathways leave
very little margin of error.
Developing Age-specific Dosing Regimens



Official prescribing information usually does not have
pediatric dosing regimens.
Developmental status adjusted regimens are highly
specific for a given agent.
Use of established compendia and published guidelines
provide the most reliable method of selecting an
appropriate therapeutic agent and adjusting dose.
Geriatric Pharmacology - What’s unique?
Physiology

Changes in underlying physiology occurs over time.





Even “healthy” elderly have diminished capacities.
Aging is a continuum and the aged are stratified by
degree of age.




Altered, usually diminished, receptor sensitivity and
responsiveness
The ability to mount a compensatory physiologic response is
diminished.
Normal homeostatic mechanisms are blunted and sometimes
produce inappropriate responses.
Young old is 65 – 75 years
Old – 75 – 85 years
Old old – age > 85 years
As age progresses so do the exceptional considerations.
Geriatric Pharmacology - What’s unique?
Physiology

Body composition


CNS





 total body water,  lean body mass,  body fat;  serum
albumin,  -1 acid glycoprotein
 weight and volume of the brain
 sensitivity to depressant drugs: ethanol, anticholinergic
effects, antipsychotic agents.
CNS effects and side effects are exaggerated
Delirium and dementia complicate therapy.
ANS


Responsiveness and appropriate reflex effects are diminished.
Orthostatic hypotension - frequent side effect due to diminished
capacity for response to agents with any degree of sympathetic
blockade.
Geriatric Pharmacology - What’s unique?
Physiology

Cardiovascular






 -adr receptor activity,  baroreceptor activity
Cardiac output is generally fairly well maintained
Cardiac disease and reserve capacity diminish with age.
Adrenergic receptor sensitivity is altered.
Any pro-arrhythmic side effect can be accentuated.
Endocrine



Atrophy of thyroid
 incidence of diabetes mellitus
Menopause, andropause
Geriatric Pharmacology - What’s unique?
Physiology

Digestive tract


 gastric emptying time,  GI blood flow;  gastric pH,
 intestinal transit time.
Hepatic


 liver size,  hepatic blood flow.
Some hepatic functions are better preserved than others.
•  albumin
• Alcohol use, gallstones, cholangitis, fatty liver (NASH),
heart failure, and conditions requiring concomitant drugs
can affect metabolism.
Geriatric Pharmacology - What’s unique?
Physiology

Renal



Pulmonary


 GFR,  renal blood flow,  tubular function
Renal function and size diminishes with age.
 respiratory muscle strength,  chest wall compliance,  total
alveolar surface
Most systems are more affected by disease than age
alone.
Geriatric Pharmacology - What’s unique?
Disease

The elderly accumulate diseases.
Geriatric Pharmacology - What’s unique?
Polypharmacy

With the accumulation of disease these is an
accumulation of treatments




Disproportionate use of drugs in the elderly.



“Polypharmacy” Multiple medications for multiple chronic
diseases
Multiple physicians
Self-medication
12% of population receive 30% of all prescriptions.
2/3 use 1 or more drugs daily.
• Ave 5 - 12 drugs daily
• < 5% use no drugs.
• 1/3 use 1 or more psychotropic drugs each year.
It is often difficult to distinguish between disease and
adverse drug events.
Geriatric Pharmacokinetics - Absorption

Age related changes are small.






Gastric/intestinal motility 
Surface area and blood flow 
Net negligible change in absorption
Less significant than disease-specific changes.
Effects of age on absorption for delayed and sustained
release formulations have not been well-documented.
A diminished first-pass effect results in an increased
bioavailability.
Geriatric Pharmacokinetics - Distribution

Lean body mass and body water 




Increased fat serves as a repository for fat soluble drugs



Vd (volume of distribution)  for water soluble drugs
Water soluble drug - conc. 
• Ex. ethanol
Fat soluble drugs  conc.
Ex. Amiodarone, desipramine, diazepam, haloperidol, digitoxin
Impact on drug therapy in general is not great.
Protein binding to albumin and -1 acid glycoprotein is
more affected by disease than age.

Decreased albumin can result in increased free fraction of drugs.
• Increased delivery to receptor
• Increased drug interactions
Volume of Distribution by Age
Geriatric Pharmacokinetics - Metabolism

Phase II reactions are better preserved than Phase I.



Note on syllabus.
Disease and environmental factors have a greater
impact on hepatic drug metabolism than age.
High extraction drugs may have decreased clearance
attributable to diminished hepatic blood flow.
Antipyrine Clearance
Geriatric Pharmacokinetics - Elimination






Renal Elimination
 Cl and  t1/2 for renally cleared drugs and metabolites.
The age-related change in renal clearance is the
most consistent and predictable change in
pharmacokinetics.
The dose of most drugs that are renally cleared should
be adjusted for renal function.
The adjustment method most frequently used is the
Cockroft-Gault equation to estimate renal clearance.
This method is not without problems, but is simple and
readily applicable in most situations.
Estimating Renal Function



Cockcroft Gault estimation
Assumes steady state production of creatinine.
Very limited utility in critically ill, clinically unstable,
malnourished or wasted patients.


Measure creatinine clearance or use extrinsic marker if critically
important.
Other formulas may be more accurate in special populations.
CLCr (ml/min) =
(140 – age) (lean weight in kg)
72 (serum creatinine in mg/dL)
(multiply by 0.85 for women)
Geriatric Pharmacokinetics - Renal Function

Drugs with predominantly renal elimination and
potentially serious toxic effects should have dosing
adjusted based on renal function.
Geriatric Pharmacokinetics – Drug Elimination

Drug dosing requires adjustment for changed
pharmacokinetic parameters.
0.693 X Vd
t 1/2 =
Clearance
Vd is smaller for water soluble drugs
Clearance is usually diminished with age
Geriatric Pharmacodynamics

Receptor alteration with age best documented for
adrenergic receptors and autonomic nervous system.




Increased sensitivity to sedation.
Increased sensitivity to hypotensive (side) effects due to
decreased baroreceptor function.
Diminished adaptive capacity most manifested as increased
occurrence of adverse events with medications.
Treatment of elderly patients can be very complex
because of multiple diseases and drug therapies that
can produce adverse drug reactions.
Appropriate Prescribing for Geriatric Patients






Obtain a complete drug history
Avoid prescribing before a diagnosis is made
Review medications regularly and before prescribing a
new medication
Know the actions, adverse effects, and toxicity profiles of
he medications you prescribe
Start low dose and titrate dose based on tolerability and
response
Geriatric dictum:
“Start low and go slow”
Appropriate Prescribing for Geriatric Patients






Educate patient and/or caregiver about each medication
Avoid using one drug to treat the side effects of another
Attempt to use one drug to treat two or more conditions
Use combination products cautiously
Communicate with other prescribers
Avoid using drugs from the same class or with similar
actions
How do you adjust drug therapy for
special populations?
Drug Information

On-line decision support



Institutional: CPOE (Computerized Physician Order Entry)
Guidelines, rules, protocols
Text-based (online and print)

Secialized information
• Johns Hopkins: The Harriet Lane Handbook: A Manual for Pediatric House
Officers, 16th ed © 2002 Mosby, Inc.
• Geriatrics At Your Fingertips, 2005 by D Reuben, and Others. The American
Geriatrics Society (AGS)


Literature (Medline, full-text, etc)
Exceptions



Investigational drugs
• NME (New Molecular Entity)
• Indication not labeled
• Literature, FDA, Sponsors
Unusual patients (age, disease, indications)
International patients (online resources, Pharmaceutical regulatory
agencies)
Drug Information Age-specific


FDA, Government and professional organizations web
sites
Medical departments of Pharmaceutical Manufacturers


Most have available physicians who have specialized knowledge
of products
Different constraints on information sharing when physician-tophysician
Case Study - 1

NICU, 32 week infant; 1 wk p delivery, wt 1800 gm
Apparent pneumonia, worried about sepsis; blood
culture growing MRSA; intermediate vancomycin
sensitivities
Is Linezolid a therapeutic alternative in this patient?

What information do you need to gather?


Case 1

Has there been documented efficacy for the medication
for the disorder in newborn or older infants/children?



Is the drug approved for pediatric use?
Is the drug approved for this indication?
Is it approved for this indication in pediatrics?
• Look in the Official Product Information
• On-line sources: Manufacturer, FDA
• Other compendia: MicroMedex, Epocrates
• Note: The FDA may be revising OPI format.
• See FDA announcement:
• <http://www.fda.gov/cder/regulatory/physLabel/default.ht
m>
OPI
Official Product Insert (Approved labeling)


Description
Clinical Pharmacology








Pharmacokinetics
• Absorption, Distribution, Metabolism, Excretion
• Special populations: Geriatric, pediatric, gender, renal
insufficiency, hepatic insufficiency
Drug-drug interactions
Special: Antibiotics|Microbiology
Indications and Usage
Contraindications (do not use)
Warnings (use with caution)
Precautions (during therapy)
Information for patients
Labeling, cont’d.

Interactions



Use in special populations or extraordinary
considerations




Drug-drug
Drug-laboratory
Pediatric, geriatric
Carcinogenesis, mutagenesis, impairment of fertility
Pregnancy; teratogenesis, lactation
Other pharmacology

Animal studies
Labeling, cont’d.

Adverse Reactions








Signs, symptoms, laboratory changes, etc
Post-marketing experience
Toxicity and Overdose
Abuse and dependence
Dosage and Administration
How supplied
Clinical Studies
References
Case 1. Cont’d.

Recognized text books either hard print or online
sources



Ex. Johns Hopkins: The Harriet Lane Handbook, The Sanford
guide to antimicrobial therapy
Official guidelines
Is the data from adequate clinical trials (randomized,
controlled, size, power, similar age/maturity)?
•
•
•
•
Approved labeling
Official guidelines (www.guidelines.gov)
Some compendia will list sources
Medline or other primary literature resources
Case 1, cont’d




Have the pharmacokinetics been established in similarly
aged children?
Has the pathway of drug clearance been established in
children/infants?
Is that pathway established in the child/infant you are
treating (based on maturity or physical state)?
Is there reason to believe that pathway may be
compromised in the specific child/infant (genetics,
disease state, concomitant therapy)?



Official compendia
Secondary sources
Primary literature (animal studies are not reliable for most
metabolic data)
Metabolism
Metabolism
Pediatric kinetics
Elderly NO
Case 1, cont’d



Is there a safe route to administer the drug? (intact GI
tract, central access, intact skin, nontoxic solvent)
Is displacement an issue for albumin binding or bilirubin
displacement?
Are there technical issues surrounding administration,
e.g. solvents, preservatives, volume?
If there is no “Approved labeling”


Official compendia, professional organizations, published
guidelines, adequate clinical trials, “standard of care”,
etc. are usually sufficient.
In dire circumstances in the absence of published
information extraordinary resources may be necessary.



Manufacturer’s Medical Department
Investigators
International sources
Summary: Pediatric pharmacology



Children and infants, especially neonates, have different
pharmacokinetic parameters than adults
Appropriate drug therapy cannot be assumed to identical
to adults, even when adjusted for weight or body surface
area.
Each agent is unique and requires adequate clinical
studies before a drug can safely be used in children.
Summary - Geriatric pharmacology


Normal homeostatic mechanisms are blunted and
sometimes produce inappropriate responses.
Metabolism and renal elimination are most often
impacted
• Phase II drug metabolizing reactions are better preserved
than Phase I.
• The dose of most drugs that are renally cleared should be
adjusted for renal function.
• Cockroft-Gault equation is frequently used to estimate
renal function.
Summary - Geriatric pharmacology cont’d






Disease and environmental factors have a greater
impact on hepatic drug metabolism than age.
Therapeutic plan should include only agents with
established efficacy.
Most drugs should started at lower doses and titrated
more slowly.
Frequent review of the complete therapeutic plan to
minimize interactions and side effects.
Adverse drug effects can mimic disease and should be
included in the evaluation of a patient.
“Drugs are the great imitator of disease”
C.R.C. Wyndham, MD
Questions?

Blair Holbein, Ph.D.
• Presbyterian Hospital of Dallas
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Email: [email protected]
Website: http://phdres.caregate.net
Annotated bibliography
Slides
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April 29 :
• Age and Pharmacokinetics: Pediatric and Geriatric
Considerations
May 2:
• Drug Interactions
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