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Pediatric Pharmacology

Pediatric Pharmacology. Philip D. Acott, MD, FRCPC Pediatric Nephrologist and Endocrinologist Professor of Pediatrics and Pharmacology April 2, 2008. Objectives. Children are not little adults Body compartments Absorption and distribution issues Renal elimination Hepatic elimination

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Pediatric Pharmacology

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  1. Pediatric Pharmacology Philip D. Acott, MD, FRCPC Pediatric Nephrologist and Endocrinologist Professor of Pediatrics and Pharmacology April 2, 2008

  2. Objectives • Children are not little adults • Body compartments • Absorption and distribution issues • Renal elimination • Hepatic elimination • Fetal exposures • Pediatric Case • Toxicity • Common drugs • Institutional issues • CNS example

  3. Developmental Pharmacology Scaling adult doses to infants based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.

  4. Drug Use in Infants and Children • developmental changes are often discovered when unexpected or severe toxicity in infants and children • Scaling adult doses based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity. • Pharmacologic impact leads to detailed pharmacologic studies. • Therapeutic tragedies could be avoided by performing pediatric pharmacologic studies during the drug development process (before wide-spread use of agents in infants and children).

  5. Ontogeny and Pharmacology • Excretory organ (liver and kidneys) development has the greatest impact on drug disposition (pharmacokinetics) • The most dramatic changes occur during the first days to months of life • Anticipate age-related differences in drug disposition based on knowledge of ontogeny • Effect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamics) is poorly studied • Disease states may alter a drug’s PK/PD

  6. Factors Affecting Drug Distribution • Physicochemical properties of the drug • Cardiac output/Regional blood flow • Degree of protein/tissue binding • Body composition • Extracellular water • Adipose tissue

  7. Ontogeny of Body CompositionKaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992 Protein Other EC H2O IC H2O Fat % of Total Body Weight

  8. Plasma Proteins

  9. Volume of Distribution of SulfaRoutledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994 Newborn Infant Children Adults Elderly 0 0.1 0.2 0.3 0.4 0.5 0 0.1 0.2 0.3 0.4 0.5 Volume of Distribution [L/kg]

  10. 17.3 Protein Binding in Cord and Adult PlasmaKurz et al., Europ J Clin Pharmacol II:463-7, 197 30.2 7

  11. Tissue and Organ Weight

  12. CNS Growth and DevelopmentBleyer, Cancer Treat Rep 61:1419-25, 1977 100 100 CNS Volume 80 80 Adult Value % 60 60 Body Surface Area 40 40 20 20 Bir th 4 8 12 16 20 24 Bir th 4 8 12 16 20 24 Age (years)

  13. Renal Ontogeny • Glomerular filtration rate • Low at birth • GFR doubles by 1 week of age • Adult values by 6-12 months of age • Tubular function • Secretory function impaired at birth • Glomerulo-tubular imbalance • Adult values by 1 year of age

  14. Gentamicin ClearancePons et al, Ther Drug Monit 10: 421-7, 1988 Premature (<37 weeks) Full term Postnatal Age Gentamicin Clearance [L/kg•hr]

  15. Maturation of Renal Function • fetal nephron development complete by 32wks gestational age • at birth, renal function is related to gestational age rather than birth weight, length or body surface area • the nephron matures after birth due to secretory load, regardless of GA

  16. Proximal Tubular Function • rates of reabsorption of glucose, phosphate, bicarbonate and amino acids are lower (Fanconi’s profile) • lower renal threshold for HCO3 and glucose • serum phosphate increased due to transient hypoparathyroidism • infants have higher serum phosphate than older child and adults • serum calcium decreased

  17. Distal Tubular Function • acidification mechanisms intact • can reduce urine pH to 4.8 and excrete acid load • reduced ability to concentrate urine maximally but can dilute • immature handling of Na leads to inc. secretion, prolonged in premature babies

  18. Urine Output • 30% of babies void at birth or soon after • 92% in 24h, 99% in 48h • in first 2 days 15cc/kg/ day • oliguria <1cc/kg/h • can also be polyuric- wt. loss>10%-DI

  19. GFR and Creatinine • GFR quite low at birth and then slowly increases • reaches adult levels (corr. to 1.73 m2) by 12-18 mos. • Creatinine higher the more premature the baby & take longer to stabilize • Creatinine values reflect maternal levels for first few days

  20. Chen et al, Pediatr Nephrol (2006) 21: 160-168

  21. Figure 1 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  22. Figure 2 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  23. Figure 3 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  24. Figure 4 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  25. Figure 5 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  26. Figure 6 Chen et al, Pediatr Nephrol (2006) 21: 160-168

  27. Hepatic Ontogeny • Phase 1 (oxidation, hydrolysis, reduction, demethylation) • Activity low at birth • Mature at variable rates • Oxidative metabolism increases rapidly after birth • Alcohol dehydrogenase reaches adult levels at 5 yrs • Activity in young children exceeds adult levels • Phase 2(conjugation, acetylation, methylation) • Conjugation: • Glucuronidation: - at birth • Sulfatation: ­ at birth • Acetylation: - at birth • “fast” or “slow” phenotype by 12-15 mo.

  28. Cytochrome P450 (CYP) Enzymes • Superfamily of Phase 1 enzymes (oxidation, demethylation) • Nomenclature: • 17 Families and 39 subfamilies in humans • CYP1, CYP2, CYP3 are primary drug metabolizing enzymes • Half of all drugs metabolized by CYP3A subfamily • CYP3A4 is most abundant hepatic P450 enzyme and metabolizes at least 50 drugs Family (>40%) Subfamily (>55%) CYP3A4 Isoform

  29. Cytochrome P450 Enzymes

  30. CYP3A Ontogeny LaCroix D et al. Eur J Biochem 247:625, 1997 CYP3A7 Activity CYP3A4 Activity >1yr 1-7d <24h Adult <30w >30w 8-28d 1-3mo 3-12mo Fetus Postnatal Age

  31. Clearance [ml/min/kg] 20 100 70 Theophylline Urinary Metabolites Post-conception Age Age Range % Recovered in Urine

  32. G:S kel 0.3 0.15 0.75 0.17 1.6 0.19 1.8 0.18 Acetaminophen MetabolismMiller et al., Clin Pharmacol Ther 19:284-94, 1976 % of Dose

  33. Pregnancy – Fetal Exposure • Therapeutic • Steroids with congenital adrenal hyperplasia • Maternal Medications that can’t stop • Thyroxine • Immunosuppressants • CNIs, steroids, azathioprine OK • MMF stopped • Inadvertent Exposures • Eg. ACE inhibitors, ARBs etc • Lifestyle & Recreational Drugs • Cocaine, amphetamines, etc • Disasters • thalidomide

  34. Bisphosphonate Use in Pediatric Patients An example of novel therapy and opportunity for investigation

  35. Case Presentation # 1 • J.L. >> Dec 1995; age 13.05 yr • Multiple Relapsing Nephrotic # 14 • Previous cyclophosphamide & chlorambucil • Biopsies x 3 >> MCD • Fell out of bed • T6,10, 12 Compression # (? New vs Old) • Initial BMD z score = - 2.25

  36. Corticosteroid-induced bone lossnonpharmacological approaches • lowest corticosteroid dose possible • alternative steroid delivery • eg. inhaled steroids • exercise • reduction of risk of falling

  37. Corticosteroid-induced bone losspharmacological approaches • HRT • Calcium and Vit D • Calcitonin • Bisphosphonates

  38. Bisphosphonate Pharmacology • Poor oral availability • Short t1/2 (1-3 hrs) in serum • Long t1/2 (years) in bone • 50% renal excreted • 50% bone absorbed

  39. *Adults given pamidronate 1 mg/kg/dose typically achieve peak pamidronate levels of 2 – 3 mg/l

  40. Idiopathic Hypercalcemia of Infancy • 9 mon ♀ with FTT, developmental delay, dehydration, vomiting, constipation (not Williams’s Syndrome) • Ca = 3.75 mmol/l (normal 2-1 -2-7) • PTH undetectable • 25 hydroxy vit D = 497 nmol/l (normal 125-250) • 1,25 dihydroxy vit D = 94 pmol/l (normal 40-140) • Hypercalciuria and nephrocalcinosis • Osteocalcin reduced

  41. Pamidronate 1 mg/kg/dose IV

  42. Radiographs after pamidronate therapy Idiopathic Hypercalcemia of Infancy - age 2.37 years Pamidronate given at 0.79, 0.85, 0.90, and 1.01 yr Pamidronate given at 1.89, 2.06, 2.21, and 2.26 yr

  43. Cyclosporin A Distribution in Brain, Liver, and Kidneys of Developing Mice: Implications for Risk of Neurotoxicity and Nephrotoxicity Goralski KB, Acott PD, Fraser AD, Worth D, Sinal CJ: Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression. Drug Metab Dispos. 2006 Feb;34(2):288-95.

  44. Pediatric Clinical Problem • Pediatric Renal transplantation is treatment of choice for children with end-stage renal failure • Seizures are common (17%) in first month post renal transplant • More common in younger children

  45. Background and Hypothesis • Drug interactions in pediatric renal transplant patients can precipitate central nervous system (CNS) toxicity, behavioral disturbances and interruptions in immunosuppressive therapy. Nephrotoxicity is commonly associated with CNIs. • P-glycoprotein (P-gp) encoded by the gene ABCB1 (MDR1) in humans and abcb1a (mdr1a) and abcb1b (mdr1b) in mouse and rat is expressed normally in epithelial cells of several organs including the brain, liver, intestine and kidney. • The ABCB1 transporters play a key role in the absorption, elimination and tissue distribution of the primary immunosuppressants (CyA, tacrolimus and methylprednisolone) used in solid organ transplant • Circumstances that impair P-gp-mediated drug transport may lead to decreased elimination, or altered entry of immunosuppressant drugs into the CNS. • We hypothesize that neonatal and developing mice with less expression of mdr1a will be less protected against CyA accumulation in the brain. The increased drug accumulation could then have implications for nephrotoxixity and adverse CNS drug effects in infants or children post organ transplant.

  46. Maturational changes in drug transporter function Drug metabolism and distribution in neonates and children • Drugs are handled differently by children than in adults • Absorption, pH, gastric emptying • Drug Metabolism cytochrome P450s • Renal function: filtration and secretion • Drug efficacy/toxicity

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