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Clinical Pharmacokinetics and Medication Use in Pediatric Patients

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.

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Clinical Pharmacokinetics and Medication Use in Pediatric Patients

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  1. 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

  2. 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

  3. 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

  4. Gaps in Healthcare • No dosage guidelines for many drugs • Unlicensed or off-label drug use common • Optimal treatment guidelines (EBM)?

  5. 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

  6. 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

  7. Common Reasons • Cost vs. potential revenue • Delay in drug approval • Ethical/practical challenges • Will use the drug anyway

  8. 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)

  9. 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?

  10. Goals of Pharmacokinetics and Pharmacodynamics • Improve efficacy • Decrease toxicity • Minimize interactions • Enhance convenience/compliance • Reduce cost

  11. Developmental Changes in Drug Clearance CLEARANCE PER KG

  12. AGENT Chloral hydrate Midazolam Ketamine Propofol Etomidate Dexmedetomidine AGE Children 6 months 16 years 3 years (induction) 2 months (maintenance) 10 years 18 years FDA Approved Labeling

  13. 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

  14. Examples of differences between Children and Adults • Anatomic ( BSA, Body Size) • Physiologic ( metabolism, BP and immunity) • Developmental (communication barriers) • Emotional (variable and challenging)

  15. Drug Absorption in Infants • Oral absorption (pH dependent passive diffusion and gastric emptying) • Intramuscular absorption (variable) • Percutaneous absorption (increased) • Bioavailability studies limited

  16. 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

  17. Drug Distribution PatientsECF (%BW) Premature infants 50% 4-6 month infant 35% Children 25% Adults 19%

  18. Tobramycin PK in Neonates

  19. 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

  20. 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)

  21. 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

  22. Phenytoin Dosage Requirement in Acute Neurotrauma( Bahal, Nahata et al. Crit Care Med 1995) Age, yearsDose, mg/kg/d 0.5 - 9 8 - 10 10 - 16 6 - 8

  23. 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

  24. Amlodipine Efficacy in HTN(Tallian, Nahata et al. Pediatr Nephrol 1999) Dosemg/kg/d Starting 0.07 + 0.04 Titrated (<13 yr) 0.29 + 0.11 Titrated (>13 yr) 0.16 + 0.11 ____________________________________________________________________________________________________________ • ADRs: Fatigue, headache, and edema • QOL: Improved activity, functioning and overall health

  25. Amlodipine Efficacy

  26. Vancomycin PK in Infants Maintenance dose (mg/kg/day) Postconceptional age (weeks)

  27. Dosage Requirements (mg/kg/d)in Pediatric Population • Premature newborns (lowest) • Full term newborns • Infants • Children (highest) • Adolescents • Adults

  28. 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

  29. 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

  30. 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

  31. Drug Safety • Aminoglycosides • Fluoroquinolones • Tetracyclines • SSRIs, ADHD drugs • Excipients (propylene glycol, sorbitol, and benzyl alcohol) • Drug interactions

  32. Challenging Pediatric Conditions • Obesity • Type 2 diabetes • Hypertension • Lipid disorders • Behavioral/neuropsychiatric disorders (e.g., ADHD, eating disorders, depression, autism, bipolar and sleep disorders)

  33. 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?

  34. 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

  35. 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

  36. 25% of ADEs Preventable(LOS attributed: 3 days)(Temple, Nahata et al. Drug Safety 2004)

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

  38. 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)

  39. 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

  40. 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?

  41. Medication Adherence • Consider factors affecting adherence • 60% in asthma (80% had preventable exacerbations) • Diabetes (insulin injections) • Poor communication especially during teenage years

  42. Molecular Diagnostics of Pharmacogenomic Traits (Science 1999; 286: 487-91) • Disease genotypes • Host susceptibility genotypes • Infection defense genotypes • Drug metabolism genotypes

  43. 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)

  44. Captopril Stability(Nahata et al. AJHP 1994) FormulaTempStability 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. The Internet • Thousands of health-related sites • Single search engine request for HIV/AIDS brought 96,000 Web addresses • Reliability?

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