Clinical Pharmacokinetics and Medication Use in Pediatric

Patients

Dr. Milap C. NahataProfessor and Chairman

Pharmacy Practice and AdministrationProfessor 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 off-label 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

Developmental Changes in Drug Clearance

CLE

AR

AN

CE

PE

R K

G

FDA Approved Labeling

AGENT• Chloral hydrate• Midazolam• Ketamine• Propofol

• Etomidate• Dexmedetomidine

AGE

Children≥ 6 months≥ 16 years≥ 3 years (induction)≥ 2 months (maintenance)≥ 10 years≥ 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 ( BSA, Body Size)

• Physiologic ( metabolism, BP and immunity)

• 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 Dose, mg/kg/d

0.5 - 9 8 - 10 10 - 16 6 - 8

Amlodipine Pharmacokinetics(Flynn, Nahata, et al J Clinical Pharmacol 2006)

Parameter 1-6 yr. 6-13 yr. 13-18 yr.

(n=11) (n=34) (n=28)

Clearance 1.0 ± 0.33 0.63 ± 0.36 0.40 ± 0.16

(L/hr/kg)

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 mg/kg/d Starting 0.07 + 0.04

Titrated (<13 yr) 0.29 + 0.11Titrated (>13 yr) 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

Vancomycin PK in Infants

q18h q36h q24h q12h q8h

24 26 28 30 32 34 36 38 40 42 44 46 48 50

45

40

35

30

25

20

15

10

5

0

Maintenance dose (mg/kg/day)

Postconceptional age (weeks)

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)

43.0%

31.0%

21.0%

3.5%

1.5%

Ordering

Administration

Monitoring

Dispensing

Transcribing

Drug Class and ADEs (Temple, Nahata et al. Drug Safety 2004)

9%

11%

12%

27%

Antineoplastics

Anticonvulsants

Opioids

Antibiotics

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 Temp Stability

Captopril, 1 mg/mL

Ascorbic Acid,

5 mg/mL 4OC 8 weeks

in distilled water 22OC 4 weeks

Captopril, 1 mg/mL 4OC 2 weeks

in purified water 22OC 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, 9% goldenseal each

Valerian root, 5% ephedra each

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 ResearchersPatients