Pharmacokinetics and pharmacology of drugs in children Saskia N. de Wildt Professor of Clinical Pharmacology Pediatric Intensivist-Clinical Pharmacologist
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
Magnitude of the problem Tan et al. MJA 2003
Fatalities in children 1959 2007
From drug to effect
Understanding pediatric PK and PD Absorption Metabolism Distribution Effect Excretion
Age and critical illness
Age and pharmacokinetics
Kearns et al NEJM, 2003
Paracetamol oral bioavailability 100 90 80 70 60 50 40 30 20 10 0 Kleiber, Mooij et al, manuscript in preparation
Age and distribution volume 100 80 60 40 TBW ECW Body Fat 20 0 Birth 3 mo 6 mo 9 mo 1 yr 5 yr 10 yr 20 yr 40 yr
Age and gentamycin peak levels Peak Gentamicin Ccn (mg/l per mg/kg dose) 3.5 3 2.5 2 1.5 1 0.5 0 infant child adolescent adult
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
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
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
CYP3A: Effect of age on tacrolimus doses Younger vs older children: kidney p = 0.003 liver p = 0.04 de Wildt et al, 2009, EJCP, Giisen V et al, JHT 2011
Age affects renal clearance Drug Transport? Kearns GL et al NEJM 2003
Maturation renal clearance 60 30 50 25 Methicillin Peak Levels 40 30 20 20 15 10 Kanamycin Peak Levels 10 5 0 0 24 h 4-5d 8-9d 13-15 d 16-30 d
Critical illness and pharmacokinetics
3. Roberts JA et al. Lancet Infect Dis. 2014;14(6):498-509. Background critical illness Underdosing: microbial resistance, suboptimal therapy, longer length of stay, morbidity and/or mortality
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
Results target attainment - patients
Results target attainment - patients N. Meningitidis MIC (0.125 mg/l): 35/37 patients with all samples >MIC (94.6%)
Results target attainment - patients N. Meningitidis 4xMIC (0.5 mg/l): 33/37 patients with all samples >MIC (89.2%)
Results target attainment - patients Enterobacter/S.pneumoniae MIC (2 mg/l): 26/37 patients with all samples >MIC (70.3%)
Results target attainment - patients S.Aureus MIC (4 mg/l): 21/37 patients with all samples >MIC (56.8%)
Results target attainment - patients Enterobacter/S.pneumoniae 4xMIC (8 mg/l): 17/37 patients with all samples >MIC (45.9%)
Results target attainment - patients S.Aureus MIC (16 mg/l): 7/37 patients with all samples >MIC (18.9%) Hartman et al, Submitted
3. Roberts JA et al. Lancet Infect Dis. 2014;14(6):498-509. Background critical illness Underdosing: microbial resistance, suboptimal therapy, longer length of stay, morbidity and/or mortality Overdosing: toxicity, possibly morbidity and/or mortality
Inflammation and organ failure affect mida PK CRP model Organ failure model 300 mg/l 100 mg/l 32 mg/l 10 mg/l 4 3 2 1 Vet et al, AJRCCM 2016
Age and critical illness
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
Understanding pediatric PK and PD Absorption Metabolism Distribution 2. Pediatric Effect PD Pain/sedation Excretion
Paracetamol for major surgery? Ceelie et al. JAMA 2013
Ceelie et al. JAMA 2013 Paracetamol group 66% less morphine Cumulative morphine amount in mcg/kg P<0.05 Paracetamol Morphine
Daily sedation interruption (DSI)? Adults: Less ventilated days Less posttraumatic stress % of pts ventilated Intervention Control Day Kress et al, NEJM, 2000
Sedation in PICU Distress Comfortable Oversedated Proportion of observations Vet et al. Intensive Care Med 2013
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
GAPP: gabapentin for neuropathic pain Children with chronic neuropathic pain Moderate pain RCT Gabapentin vs tramadol Severe pain RCT Morphine+gabapentin vs Morphine+placebo
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 21 5-15 kg 7 14 21 42 63 >15 kg 5 10 15 30 45
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.
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 2017 1193-1120
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
Ready for a new challenge? Radboudumc is looking for: Professor of Pediatric Anesthesiology Info: saskia.dewildt@radboudumc.nl