You are on page 1of 73

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 - Whats 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 (Youngs, Clarks) 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


Premature
Neonates

Neonatal
< 1 mo.

Early
infant

Mid-Infant
35 mo.

Late infanttoddler
6 24 mo.

Older child

Dermal

Lung

PK
Pathway

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

100

Total Body Water


Extracellular Water
Body fat

80
60
40
20
0
0

3 mo.

6 mo.

9 mo.

1 yr

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

Ginsbergetal.Pediatrics2004;113:973.

Relative Half-lives of CYP3A Substrates

PEDIATRICS Vol. 113 No. 4 April 2004, pp. 973-983

Developmental Pharmacology -Metabolism:


Phase I
PK Pathway

Premature
Neonates

Neonatal
< 1 mo.

Early
infant

Mid-Infant
35 mo.

Late infanttoddler
6 24 mo.

Older child

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

Metabolism:
Phase I

Developmental Pharmacology - Metabolism:


Phase II
PK Pathway

Premature
Neonates

Neonatal
< 1 mo.

Early
infant

Mid-Infant
35 mo.

Late infanttoddler
6 24 mo.

Older child

Glucuonidation

N-acetylation

Metabolism:
Phase Ii

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
120
100
80
60
Glomerular
Filtration Rate
PAH Clearance

40
20
0
1-2
days

2-4 wk

2 mo

6 mo

1 yr

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 - Whats 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 - Whats 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 - Whats 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 - Whats 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 - Whats 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 - Whats unique?


Disease

The elderly accumulate diseases.

Geriatric Pharmacology - Whats 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, contd.

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, contd.

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. Contd.

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, contd

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, contd

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.

Manufacturers 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 contd

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

Email: bholbein@hcin.net
Website: http://phdres.caregate.net
Annotated bibliography
Slides

April 29 :
Age and Pharmacokinetics: Pediatric and Geriatric
Considerations
May 2:
Drug Interactions