Transcript Temple, Nahata et al. Drug Safety 2004

Clinical Pharmacokinetics and
Medication Use in Pediatric
Patients
Dr. Milap C. Nahata
Professor and Chairman
Pharmacy Practice and Administration
Professor of Internal Medicine and Pediatrics
Ohio State University College of Pharmacy
Definitions
• Gestational age (GA): conception to
birth
• Premature infant: born < 36 weeks GA
• Neonates: 1 day to 1 month of age
• Infants: 1 month to 1 year of age
• Children: 1 to 12 years of age
• Adolescents: 12 to 16 years of age
Advances in Science
and Technology
• Infant mortality lowest (6.8/1,000 births)
• Overall mortality and morbidity lowest
(Polio 33,000 in 1950 vs 1 in 1998)
• Lessons learned (thalidomide,
chloramphenicol, sulfonamides,
isotretinoin, promethazine)
• PK/PD, efficacy, and safety depend on
maturation; more studies needed
Gaps in Healthcare
• No dosage guidelines for many
drugs
• Unlicensed or off-label drug use
common
• Optimal treatment guidelines
(EBM)?
Most Common Disclaimer
for Pediatric Use
• “Safety and effectiveness in
pediatric patients have not been
established”
• Inadequate prescribing information
for over 80% of drugs approved for
adults
Unlicensed or Off-label Use of
Drugs in Pediatric Patients
(BMJ 2000; 320:79-92)
• 67% of children in hospitals
receive drugs in unlicensed or offlabel manner
• 90% of infants in ICU receive
unlicensed/off-label drugs
Common Reasons
• Cost vs. potential revenue
• Delay in drug approval
• Ethical/practical challenges
• Will use the drug anyway
Pharmacokinetics/Pharmacodynamics
• Pharmacokinetics
– What the body does to the drug
(Absorption, distribution, metabolism and elimination)
• Pharmacodynamics
– What drug does to the body
(e.g., change in blood pressure)
Clinical Applications of
Pharmacokinetics
• Is the drug well absorbed?
• Does it reach target site?
• What dose and frequency?
• Interactions with drug(s)/food?
• Dosage in renal/liver or other disease?
• Concentration – effect relationship?
Goals of Pharmacokinetics and
Pharmacodynamics
• Improve efficacy
• Decrease toxicity
• Minimize interactions
• Enhance convenience/compliance
• Reduce cost
CLEARANCE PER KG
Developmental Changes in Drug
Clearance
FDA Approved Labeling
•
•
•
•
AGENT
Chloral hydrate
Midazolam
Ketamine
Propofol
AGE
Children
≥ 6 months
≥ 16 years
≥ 3 years (induction)
≥ 2 months (maintenance)
• Etomidate
≥ 10 years
• Dexmedetomidine ≥ 18 years
What is an “Ideal Agent”?
• Minimizes physical discomfort/pain
• Rapid and consistent onset
• Successful completion of procedure
• Quick recovery time
• Least adverse events
• Produces amnesia
• Does not exist so practices vary
Examples of differences between
Children and Adults
• Anatomic (
• Physiologic (
immunity)
BSA,
Body Size)
metabolism,
BP and
• Developmental (communication barriers)
• Emotional (variable and challenging)
Drug Absorption in Infants
• Oral absorption (pH dependent passive
diffusion and gastric emptying)
• Intramuscular absorption (variable)
• Percutaneous absorption (increased)
• Bioavailability studies limited
Glycerol in Reye’s Syndrome
• Mortality up to 70% (1979)
• High dose IV glycerol
(0.75-1.5 g/kg/2hr) reduced
mortality from 80% to 20%
• 10-fold variability in clearance
• Optimum outcomes achieved by
concentration controlled therapy
Drug Distribution
Patients
ECF (%BW)
Premature infants
50%
4-6 month infant
35%
Children
25%
Adults
19%
Tobramycin PK in Neonates
Gentamicin Dosage Regimens
• Premature neonate
2.5 mg/kg/12-24h
• Full term neonate
2.5 mg/kg/8-12h
• Infants/child
2.5 mg/kg/8h
• From adult (weight)
1 mg/kg/8h
• From adult (BSA)
2 mg/kg/8h
Drug Metabolism
• Sulfation develops faster; glucuronidation
and oxidation takes longer
• Codeine less effective due to lower
metabolism to morphine
• Morphine also has active metabolite
• CYP2C9, 2C19, 1A2, 2D6, and 3A4 develop at
different rates (lower in infants, higher in
children versus adults)
Cytochrome P450 System
• Multiple isozymes may be involved
• Enzymes located in liver, gut, etc.
• Drugs in a class interact differently
• Drugs affecting P450 system can also
affect efflux transporter, P glycoprotein
Phenytoin Dosage Requirement
in Acute Neurotrauma
( Bahal, Nahata et al. Crit Care Med 1995)
Age, years
0.5 - 9
10 - 16
Dose, mg/kg/d
8 - 10
6-8
Amlodipine Pharmacokinetics
(Flynn, Nahata, et al J Clinical Pharmacol 2006)
Parameter
1-6 yr.
(n=11)
6-13 yr.
(n=34)
13-18 yr.
(n=28)
Clearance
(L/hr/kg)
1.0 ± 0.33 0.63 ± 0.36 0.40 ± 0.16
Vd (L/kg)
44.5 ± 12.5 27 ± 0.88
21.6 ± 6.4
Amlodipine Efficacy in HTN
(Tallian, Nahata et al. Pediatr Nephrol 1999)
Dose
Starting
Titrated (<13 yr)
Titrated (>13 yr)
mg/kg/d
0.07 + 0.04
0.29 + 0.11
0.16 + 0.11
____________________________________________________________________________________________________________
• ADRs: Fatigue, headache, and
edema
• QOL: Improved activity,
functioning and overall health
Amlodipine Efficacy
91%
42%
53%
58%
Visit 1 Visit 2 Visit 3 Visit 4
Maintenance dose (mg/kg/day)
Vancomycin PK in Infants
45
40
35
30
25
20
15
10
5
q36h
q18h
q24h
q12h
q8h
0
24
26
28
30
32
34
36
38
Postconceptional age (weeks)
40
42
44
46
48
50
Dosage Requirements (mg/kg/d)
in Pediatric Population
• Premature newborns (lowest)
• Full term newborns
• Infants
• Children (highest)
• Adolescents
• Adults
Medication Efficacy and Safety
• Neonates need pain therapy
• Dextromethorphan no more effective than
placebo for cough (> 0.5 mg/kg dose;
CYP2D6 genetic polymorphism)
• Promethazine: fatal respiratory depression
(contraindicated for < 2 yr)
• Tricyclic antidepressants more toxic in
children than adults
Azithromycin: CF with
P. aeruginosa
(JAMA 2003; 290:1749)
• Three placebo controlled studies (mean age
12-28 years) showed improvement in % FEV1
and FVC
• Dose ranged from 250 mg TIW in <40 kg to
500 mg QD x 6 months
• Guideline for <12 yr and optimal dosage
regimen unknown
Oseltamivir (Tamiflu)
(Roche Jan 5, 2004)
• Indicated for treatment and prophylaxis
• Warning in < 1 yr old due to brain conc.
of 1,500 times in 7 day old rats versus
adult animals
Drug Safety
• Aminoglycosides
• Fluoroquinolones
• Tetracyclines
• SSRIs, ADHD drugs
• Excipients (propylene glycol,
sorbitol, and benzyl alcohol)
• Drug interactions
Challenging Pediatric Conditions
• Obesity
• Type 2 diabetes
• Hypertension
• Lipid disorders
• Behavioral/neuropsychiatric disorders
(e.g., ADHD, eating disorders,
depression, autism, bipolar and sleep
disorders)
Psychiatric Emergencies
• 5-9% of youths: extreme functional
impairments (9-13% “significant”)
• Depression in 2/3 of psych. hosp.
• Lack of mental/behavioral screening
tool (ED)
• Medication selection, doses, efficacy,
safety?
SSRIs and Suicidal Ideation
• Suicidal ideation: paroxetine (3.2%)
vs. placebo (1.5%), (BMJ 2003)
• Meta-analysis (2004): relative risk
higher for paroxetine, sertraline,
citolopram and venlafaxine.
Fluoxetine vs. placebo: similar RR
Options for Antidepressant
Therapy
• TCAs may be no better than placebo
and may cause anticholinergic and
cardiac ADEs
• Higher risk of death with overdose
• SSRIs appear effective; initiate low
dose, titrate slow, adhere to avoid
too low/high conc., monitor
treatment, taper if needed
25% of ADEs Preventable
(LOS attributed: 3 days)
(Temple, Nahata et al. Drug Safety 2004)
Transcribing
Dispensing
Monitoring
Administration
Ordering
1.5%
3.5%
21.0%
31.0%
43.0%
Drug Class and ADEs
(Temple, Nahata et al. Drug Safety 2004)
Antibiotics
Opioids
Anticonvulsants
Antineoplastics
27%
12%
11%
9%
Dose Calculations: Error Potential
• Accuracy of body weight (kg vs. lb)
• Calculation of dose per kilogram
• mg vs. mcg or mg vs. mL errors
• Ten-fold decimal/calculation errors
• Combination products, dose errors (e.g.,
Tylenol with codeine)
• Tylenol syrup (120 mg/5 mL) vs. drops
(100 mg/mL)
Drug Administration
• Intravenous administration (bolus/infusion)
• Look-alike, different concentration
(e.g., heparin)
• Need for oral liquid formulations
• Transdermal formulations
• Proper use of inhalers/nebulizers
Discharge Medication
Education/Counseling
• Why use the medicine?
• How to take/give it?
• What to expect for efficacy?
• What to expect as ADEs?
• How to prevent ADEs/DIs?
• Why take as suggested?
Medication Adherence
• Consider factors affecting adherence
• 60% in asthma (80% had preventable
exacerbations)
• Diabetes (insulin injections)
• Poor communication especially during
teenage years
Molecular Diagnostics of
Pharmacogenomic Traits
(Science 1999; 286: 487-91)
• Disease genotypes
• Host susceptibility genotypes
• Infection defense genotypes
• Drug metabolism genotypes
Multi-locus Genotypes to
Select Drug Therapy
(Nature 1988: 331: 442-6)
•
•
•
•
Gene expression
Whole genome association
Proteomics
Pharmacokinetic candidate genes
(ADME)
• Pharmacodynamic candidate genes
(receptors, enzyme targets, disease
modifiers)
Captopril Stability
(Nahata et al. AJHP 1994)
Formula
Captopril, 1 mg/mL
Ascorbic Acid,
5 mg/mL
in distilled water
Temp
Stability
4OC
22OC
8 weeks
4 weeks
Captopril, 1 mg/mL
in purified water
4OC
22OC
2 weeks
1 week
Sildenafil Stability
• No oral medication for pulmonary
hypertension
• Sildenafil, 2.5 mg/ml in 1%
methylcellulose/syrup (1:1) and
OraPlus/OraSweet (1:1) stable at
4o C and 22o C for 3 months
Herbal Use: Pediatric ED Patients I
(Pediatrics 2003; 111:981-5)
• 43% of caregivers gave these to
patients, 3 week-18 years old
• 53% gave one product;
27% gave > 3 over past year
• Ephedra + albuterol most dangerous
• Unusual: turpentine, pine needles,
cow chips
Herbal Use: Pediatric ED Patients II
(Pediatrics 2003; 111:981-5)
Aloe plant/juice
44%
Echinacea
33%
Sweet oil
25%
Eucalyptus
20%
Ginkgo, ginseng,
goldenseal each
9%
Valerian root,
ephedra each
5%
Potential ADEs/DIs with Herbals
• 61% taking prescription drug
• Boost immune system in lupus: Echinacea
• Worms: turpentine rubdown and orally
• Colds: catnip, cow chip tea, pine needles
• 77% felt fully safe
• 66% unsure/thought of no DIs
• 45% informed physicians
The Internet
• Thousands of health-related
sites
• Single search engine request for
HIV/AIDS brought 96,000 Web
addresses
• Reliability?
Therapeutic Orphan
• 1962 Drug Law of FDA
• “By an odd and unfortunate twist
of fate, infants and children are
becoming therapeutic or
pharmaceutical orphans.”
H. Shirkey,1963
Federal Regulations
• Best Pharmaceuticals for Children Act
(BCPA) of 2002 (Incentive – 6 month patent
extension)
• 1998 – 2004: 37% of key labeling changes
and 26% of key safety end points
• Have published articles (JAMA 09/06)
• Pediatric Research Equity Act (PREA) of
2003 (new drugs – exceptions possible)
• Generic drugs?
Observation
• The therapeutic orphan is ready for
adoption
• Healthy upbringing would require
continued efforts
Conclusions
• Significant progress made in
diagnosis, prevention and treatment
• Advances and challenges continue
• Interdisciplinary programs important
Interdependence
Educators
Patients
Researchers