Pharmacokinetics and pharmacology of drugs in children

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2 Pharmacokinetics and pharmacology of drugs in children Saskia N. de Wildt Professor of Clinical Pharmacology Pediatric Intensivist-Clinical Pharmacologist

3 Understanding pediatric PK and PD Absorption 1. Understanding agerelated change in PK Interplay with critical illness Metabolism Distribution 2. Pediatric Effect PD Pain/sedation Excretion

4 Magnitude of the problem Tan et al. MJA 2003

5 Fatalities in children

6 From drug to effect

7 Understanding pediatric PK and PD Absorption Metabolism Distribution Effect Excretion

8 Age and critical illness

9 Age and pharmacokinetics

10 Kearns et al NEJM, 2003

11 Paracetamol oral bioavailability Kleiber, Mooij et al, manuscript in preparation

12 Age and distribution volume TBW ECW Body Fat 20 0 Birth 3 mo 6 mo 9 mo 1 yr 5 yr 10 yr 20 yr 40 yr

13 Age and gentamycin peak levels Peak Gentamicin Ccn (mg/l per mg/kg dose) infant child adolescent adult

14 Drug metabolism: midazolam as CYP3A probe Midazolam CYP3A4/5 1-OH-midazolam UGTs 1-OH-midazolam-glucuronide Midazolam clearance reflects in vitro CYP3A activity in adults Thummel et al, 1994

15 Midazolam as CYP3A probe Oral bioavailability (%) Mida clearance (ml/kg/min) Preterm Adult Preterm <6mth >6mth Adult de Wildt et al, Br J Clin Pharm 2002, Clin Pharm Ther 2001, Crit Care Med 2003

16 UGT&ST: Age affects paracetamol dosing AUC 0-inf AAP- Glu AAP- Sul Age 0-6 years (log scale) Mooij MG et al, Clin Pharmacokinei 2017

17 CYP3A: Effect of age on tacrolimus doses Younger vs older children: kidney p = liver p = 0.04 de Wildt et al, 2009, EJCP, Giisen V et al, JHT 2011

18 Age affects renal clearance Drug Transport? Kearns GL et al NEJM 2003

19 Maturation renal clearance Methicillin Peak Levels Kanamycin Peak Levels h 4-5d 8-9d d d

20 Critical illness and pharmacokinetics

21 3. Roberts JA et al. Lancet Infect Dis. 2014;14(6): Background critical illness Underdosing: microbial resistance, suboptimal therapy, longer length of stay, morbidity and/or mortality

22 Cefotaxime therapy adequate in PICU? Cefotaxime is frequently used in critically ill children as broad spectrum antibiotic therapy No data in literature of pediatric cefotaxime levels Hypothesis: low target-attainment, in line with recent literature for other antibiotics in critically ill children and adults

23 Results target attainment - patients

24 Results target attainment - patients N. Meningitidis MIC (0.125 mg/l): 35/37 patients with all samples >MIC (94.6%)

25 Results target attainment - patients N. Meningitidis 4xMIC (0.5 mg/l): 33/37 patients with all samples >MIC (89.2%)

26 Results target attainment - patients Enterobacter/S.pneumoniae MIC (2 mg/l): 26/37 patients with all samples >MIC (70.3%)

27 Results target attainment - patients S.Aureus MIC (4 mg/l): 21/37 patients with all samples >MIC (56.8%)

28 Results target attainment - patients Enterobacter/S.pneumoniae 4xMIC (8 mg/l): 17/37 patients with all samples >MIC (45.9%)

29 Results target attainment - patients S.Aureus MIC (16 mg/l): 7/37 patients with all samples >MIC (18.9%) Hartman et al, Submitted

30 3. Roberts JA et al. Lancet Infect Dis. 2014;14(6): Background critical illness Underdosing: microbial resistance, suboptimal therapy, longer length of stay, morbidity and/or mortality Overdosing: toxicity, possibly morbidity and/or mortality

31 Inflammation and organ failure affect mida PK CRP model Organ failure model 300 mg/l 100 mg/l 32 mg/l 10 mg/l Vet et al, AJRCCM 2016

32 Age and critical illness

33 Interplay age and inflammation Midazolam clearance (L/hour) 10 Bodyweight (kg) Normal >2 organs failing High CRP CRP+organ failing Vet et al. Am J Resp Crit Care Med, 2016

34 Understanding pediatric PK and PD Absorption Metabolism Distribution 2. Pediatric Effect PD Pain/sedation Excretion

35 Paracetamol for major surgery? Ceelie et al. JAMA 2013

36 Ceelie et al. JAMA 2013 Paracetamol group 66% less morphine Cumulative morphine amount in mcg/kg P<0.05 Paracetamol Morphine

37 Daily sedation interruption (DSI)? Adults: Less ventilated days Less posttraumatic stress % of pts ventilated Intervention Control Day Kress et al, NEJM, 2000

38 Sedation in PICU Distress Comfortable Oversedated Proportion of observations Vet et al. Intensive Care Med 2013

39 Pediatric DSI trial Design DSI vs protocolized sedation Intervention DSI after daily safety screen Primary outcome: ventilator-free days at 28 days Secondary outcomes: ICU length of stay Sedative doses and levels: PK Long-term: PTSD and IQ

40 GAPP: gabapentin for neuropathic pain Children with chronic neuropathic pain Moderate pain RCT Gabapentin vs tramadol Severe pain RCT Morphine+gabapentin vs Morphine+placebo

41 Dosing of Gabapentin Dosing for gabapentin will be defined according to 2 weight groups. Current dosing schedule for gabapentin is the following: Day 1 Day 3 Day 5 starting dose in mg/kg/day; 2 times the starting dose; 3 times the starting dose; Day 14 2 times the dose of Day 5; Day 21 3 times the dose of Day 5. Doses in mg/kg/day Weight group Day 1 Day 3 Day 5 Day 14 Day kg >15 kg

42 Predicted Gabapentin Exposure Red dotted lines represent target concentration range (compared to adult levels). Whisker-box plots show median values and confidence intervals; hinges depict 25 th and 75 th percentiles.

43 Metamizol efficacy and safety: systematic review Efficacy: 3 good quality RCT in children Outcome: pain scores and rescue pethidine paracetamol IV vs metamizol IV load + infusion Better than placebo, metamizole = paracetamol Safety: Risk of agranulocytosis low, but not negligible Discussion: Place in therapy questionable? de Leeuw et al, Ped Anesthesiolo

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45 Acknowledgements Erasmus MC Miriam Mooij Nienke Vet Ilse Ceelie Niina Kleiber Dick Tibboel John van den Anker Matthijs de Hoog Lonneke Staals Tom de Leeuw Radboudumc Stan Hartman Leiden University Catherijne Knibbe TNO Wouter Vaes Heleen Wortelboer Evita van de Steeg SickKid Toronto Gideon Koren Children s Mercy Hospital Greg Kearns Steve Leeder Funding Erasmus MC KNAW ZonMW EU FP7

46 Ready for a new challenge? Radboudumc is looking for: Professor of Pediatric Anesthesiology Info: saskia.dewildt@radboudumc.nl