Developmental Pharmacology

2. 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.

3. Chloramphenicol • Natural product of Streptomyces (1947) • Inhibits protein synthesis (bacteriostatic) • Eliminated by glucuronide conjugation (90%) and renal excretion (<10%) • Nursery infections treated with high doses

4. Chloramphenicol in Infants • 3320 gm infant, 44 week gestation • Meconium stained, foul smelling, timing of ROM unknown • Procaine penicillin (50,00 units) + chloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hr • Day 4, gray color & cold, moist skin • Died at 106 hr, 8 hr after onset of vascular collapse Sutherland, Am J Dis Child 97:761-7, 1959

5. Chloramphenicol in Premature Infants Premature infants born ≥24 hrs after ROM Burns et al., NEJM 261:1318-21, 1959

6. Gray Baby Syndrome Jaundice Vomiting 4 Anorexia 4.1 Resp. distress 4.3 Abd. distention 4.5 Cyanosis 4.6 Green stools 4.7 Lethargy 5 Ashen color 5.3 Death 5.7 % of Infants Burns et al., NEJM 261:1318-21, 1959

7. Chloramphenicol Blood Levels Chloramphenicol doses Total Nitro Compounds [µg/ml] Therapeutic range Day of Life Burns et al., NEJM 261:1318-21, 1959

8. t1/2 - 26 hrs t1/2 - 10 hrs t1/2 - 4 hrs Chloramphenicol Pharmacokinetics Total Nitro Compounds [µg/ml] 1-2 days (n=5) 10-16 days (n=3) 4-5 yrs. (n=3) Time [hr] Weiss et al., NEJM 262:787-94, 1960

9. Repeated Administration Total Nitro Compounds [µg/ml] Day of Life Weiss et al., NEJM 262:787-94, 1960

10. 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 of developmental changes are often discovered when unexpected or severe toxicity in infants and children 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). Drug Use in Infants and Children

11. Zidovudine • Synthetic nucleoside analog • Inhibits HIV reverse transcriptase • Eliminated by glucuronide conjugation (67%) and renal excretion (33%) • Perinatal therapy to prevent HIV transmission

12. Zidovudine in the Newborn ZDV AUC [µg•hr/ml] Age [weeks] Boucher et al., J Pediatr 122:137-44, 1993

13. Zidovudine in Newborns Boucher et al., J Pediatr 125:642-9, 1994 Mirochnick et al., Antimicrob Agents Chemother 42:808-12, 1998 Balis et al., J Pediatr 114:880-4, 1989 Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987

14. Age [weeks] Zidovudine Placebo Hemoglobin [g/dl] Prevention of HIV Transmission Connor et al., NEJM 331:1173-80, 1994

15. 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

16. Renal Ontogeny • Glomerular filtration rate • Low at birth • Full term newborn - 10-15 ml/min/m2 • Premature - 5-10 ml/min/m2 • GFR doubles by 1 week of age • Adult values by 6-12 months of age • Tubular function • Secretory function impaired at birth • Glomerulotubular imbalance • Adult values by 1 year of age

17. Glomerular Filtration Rate GFR [ml/min/1.73 m2] Age [months] Aperia, Acta Pædiatr Scand 64:393-8, 1975

18. GFR in Infants GFR [ml/min/1.73 m2] Age [days] Guignard, J Pediatr 87:268-72, 1975

19. Gentamicin in the Newborn 15 full term 23 premature Gentamicin Clearance [ml/kg•hr] Creatinine Clearance [ml/kg•hr] Koren et al., Clin Pharmacol Ther 38:680-5, 1985

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

21. 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.

22. 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

23. Cytochrome P450 Enzymes

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

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

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

27. 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

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

29. Volume of Distribution of Sulfa Volume of Distribution [L/kg] Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994

30. Tissue and Organ Weight

31. Plasma Proteins

32. 30.2 17.3 Protein Binding in Cord and Adult Plasma Kurz et al., Europ J Clin Pharmacol II:463-7, 1977

33. CSF MTX and Age CSF Methotrexate [µM] Time [days] Bleyer, Cancer Treat Rep 61:1419-25, 1977

34. CNS Growth and Development CNS Volume Adult Value [%] Body Surface Area Age [yrs] Bleyer, Cancer Treat Rep 61:1419-25, 1977

35. Adaptive IT MTX Dosing Regimen Bleyer, Cancer Treat Rep 61:1419-25, 1977

36. Dose Change with Adaptive Regimen Adaptive dose X 100 12 mg/m2 dose % Change in Dose Age [yrs] Bleyer, J Clin Oncol 1:317-25, 1983

37. Effect of Adaptive IT Dosing on Outcome MTX Dose Based on BSA 20 Concurrent 10 Incidence of CNS Relapse [%] Isolated 0 MTX Dose Based on Age 10 0 <18 18-35 36-83 84-119 ≥12 Age [months] Bleyer, J Clin Oncol 1:317-25, 1983

38. Body Weight :Surface Area Adult 1 mg/kg = 40 mg/m2 Dose = 70 mg Weight BSA 1 y.o. 1 mg/kg = 10 mg 40 mg/m2 = 18 mg Age [yrs]

39. Anticancer Drug Clearance McLeod et al., Br J Cancer 66 (Suppl. 18):S23-S29, 1992

40. Vincristine Clearance Vincristine Clearance [ml/min/m2] Vincristine Clearance [ml/min/kg] Crom et al., J Pediatr 125:642-9, 1994

41. Etoposide Clearance Etoposide Clearance [ml/min/m2] Etoposide Clearance [ml/min/kg]

42. Doxorubicin Clearance Doxorubicin Clearance [ml/min/m2] Doxorubicin Clearance [ml/min/kg]

43. Oral Busulfan (16-30 mg/kg) Engraftment Busulfan Css [ng/ml] Graft rejection Age [yrs] Slattery et al., Bone Marrow Transplant 16:31, 1995

44. Drug Clearance in Cystic Fibrosis Cystic Fibrosis Controls Hepatic Renal Clearance [ml/min•m2] Rey, Clin Pharmacokinet 35:313-29, 1998

45. Retinoids

46. Conclusions • Infants (esp. newborns) may have reduced capacity to eliminate drugs • Anticipate the effects of ontogeny on drug disposition based on route of elimination • More systematic pharmacokinetic studies of anticancer drugs in infants are needed • Tissue sensitivity to the toxic effects of anticancer drugs may be age-dependent

47. THE END