determinants of variability in disposition of exogenous compounds in neonates

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

2. conclusions 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

5. fetus developmental (dis)continuum newborn weight x 2 5 m x 3 1 y caloric needs x 3-4 1 y infant toddler child adolescent adult

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

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 Distribution exposure Elimination Metabolism patternrecognition: covariates ? 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

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

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

12. drug metabolism: relation to weight/age ?

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

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

15. distribution volume: hydrophylic drugs

16. distribution volume: lipophylic drugs

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

19. Ref: Weinshilboum, NEJM 2003

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

21. CYP3A4 CYP3A7 Testosterone 6b-hydroxylation DHEA 16a-hydroxylation drug metabolism: co-variates - age CYP3A7-CYP3A4 “Switch” 0.15 1.50 0.10 1.00 0.05 0.50 0.00 0.00 <30 wk >30 wk <24 hr 1-7 d 8-28 d 1-3 mo 3-12 mo >1 yr Adult Fetus Newborn

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

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

33. Br J Anaesth 2007

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

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

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

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