1. Karel Allegaert, MD PhD UZ Leuven determinants of variability in disposition of exogenous compounds in neonates Clinical research supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen) by a Fundamental Clinical Investigatorship (2009-2014)

2. Neonatologists are working at the fast lane of (developmental) life, age or size/weight are the most significant covariates in general, drug clearance is low. This – however – does not exclude extensive interinidividual variability within the neonatal population (size log value) This extensive interindividual variability in drug disposition necessitates the search for covariates within the neonatal population There is no such thing as ‘an isolated neonatal liver/kidney’ main route of clearance should not be similar in neonates compared to adults conclusions

5. developmental (dis)continuum fetus newborn infant toddler child adolescent adult weightx 25 m x 31 y caloric needsx 3-41 y

7. compound Exposure Response Absorption Distribution Receptor Interaction Biotransformation Excretion Absorption Distribution Receptor Interaction Biotransformation Excretion environmentalgenetics disease growth maturation extensive interindividual variability

8. developmental pharmacology PK : what the body does to the drug: conc/time PD: what the drug does to the body : conc/effect

9. Absorption Metabolism Elimination Distribution exposure The combination of ADME will determine the time/conc profile This time/conc profile together with aspects of the therapeutic target/receptor will determine the conc/effect profile pattern recognition: covariates ?

10. hepatic renal Body composition Formula dependent Ref: Kearns et al, NEJM 2003

11. Ref: Rakhmanina et al, 2006 body composition is age-dependent

12. drug metabolism: relation to weight/age ?

13. Ref: Nelson’s textbook Pediatrics brain/body fraction

14. Biol Neonate 1998;74:351-62 distribution volume: hydrophylic drugs

16. distribution volume: lipophylic drugs

18. hepatic renal Body composition Formula dependent Ref: Kearns et al, NEJM 2003

19. Ref: Weinshilboum, NEJM 2003

20. biotransformation Drug Phase I CYPs Esterases Dehydrogenases CYPs Esterases Dehydrogenases Phase II UGTs NATs STs MTs GSTs UGTs NATs STs MTs GSTs Metabolite

21. CYP3A7-CYP3A4 “Switch” 0.00 0.50 1.00 1.50 <30 wk>30 wk<24 hr1-7 d8-28 d1-3 mo3-12 mo>1 yrAdult 0.15 0.10 0.05 0.00 FetusNewborn DHEA 16  -hydroxylation CYP3A7 Testosterone 6  -hydroxylation CYP3A4 drug metabolism: co-variates - age

23. drug metabolism: ontogeny and polymorphism ?

24. drug metabolism: ontogeny and polymorphism

27. glucuronidation: postnatal age-dependent Bouwmeester et al, Br J Anaesth 2004

29. CYP2B6/3A4 34 % UGT 77 % propofol clearance is metabolic clearance High capacity, low specificity : glucuronidation Low capacity, high specificity: CYP2B6

30. propofol clearance in neonates compared to toddlers Pediatr Anesth 2007

31. Br J Anaesth 2007

32. PMA was the most predictive covariate for clearance (p<0.001) when parameterized as [CLstd x (PMA/38)11.5]. Standardized propofol clearance (CLstd) at 38 weeks PMA was 0.029 L/min The addition of a fixed value in neonates with a postnatal age of ≥ 10 days further improved the model (p < 0.001) and resulted in the equation [CLstd. (PMA/38)11.5 + 0.03 L/min] for neonates ≥ 10 days. Br J Anaesth 2007

38. hepatic renal Body composition Formula dependent Ref: Kearns et al, NEJM 2003

40. Guignard et al, J Pediatr 1975 Koren et al, Clin Pharmacol Ther 1975 GFR/postnatal ageGFR/gentamicin

42. Biol Neonate 1998;74:351-62 renal drug elimination

43. Guignard JP. Pediatr Research 1994

44. renal drug elimination: impact of age at birth

45. Guignard JP. Pediatr Research 1994

46. renal drug elimination: predictability/postnatal age

48. renal drug elimination: co-medication

49. Br J Clin Pharmacol 2007 (glycopeptides) renal drug elimination: age and NSAID’s

51. renal drug elimination: disease characteristics

53. Ref: Weinshilboum, NEJM 2003

55. extensive interindividual variability Pattern recognition age size co-medication disease characteristics polymorphisms improved predictability collaborative efforts, ‘sized’ techniques population pk low volume samples

56. Neonatologists are working at the fast lane of (developmental) life, age or size/weight are the most significant covariates in general, drug clearance is low. This – however – does not exclude extensive interinidividual variability within the neonatal population (size log value) This extensive interindividual variability in drug disposition necessitates the search for covariates within the neonatal population There is no such thing as ‘an isolated neonatal liver/kidney’ main route of clearance should not be similar in neonates compared to adults conclusions