Pediatric_Pharmacology_2April2008

Pediatric Pharmacology : 

Pediatric Pharmacology Philip D. Acott, MD, FRCPC Pediatric Nephrologist and Endocrinologist Professor of Pediatrics and Pharmacology April 2, 2008

Objectives : 

Objectives Children are not little adults Body compartments Absorption and distribution issues Renal elimination Hepatic elimination Fetal exposures Pediatric Case Toxicity Common drugs Institutional issues CNS example

Developmental Pharmacology : 

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.

Drug Use in Infants and Children : 

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

Ontogeny and Pharmacology : 

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

Factors Affecting Drug Distribution : 

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

Ontogeny of Body CompositionKaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992 : 

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

Plasma Proteins : 

Plasma Proteins

Volume of Distribution of SulfaRoutledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994 : 

Volume of Distribution of SulfaRoutledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994 0 0.1 0.2 0.3 0.4 0.5 0 0.1 0.2 0.3 0.4 0.5 Volume of Distribution [L/kg] Newborn Infant Children Adults Elderly

Protein Binding in Cord and Adult PlasmaKurz et al., Europ J Clin Pharmacol II:463-7, 197 : 

Protein Binding in Cord and Adult PlasmaKurz et al., Europ J Clin Pharmacol II:463-7, 197 7 30.2

Tissue and Organ Weight : 

Tissue and Organ Weight

CNS Growth and DevelopmentBleyer, Cancer Treat Rep 61:1419-25, 1977 : 

CNS Growth and DevelopmentBleyer, Cancer Treat Rep 61:1419-25, 1977 Bir th 4 8 12 16 20 24 20 40 60 80 100 Bir th 4 8 12 16 20 24 20 40 60 80 100 CNS Volume Body Surface Area Adult Value % Age (years)

Renal Ontogeny : 

Glomerular filtration rate Low at birth GFR doubles by 1 week of age Adult values by 6-12 months of age Tubular function Secretory function impaired at birth Glomerulo-tubular imbalance Adult values by 1 year of age Renal Ontogeny

Gentamicin ClearancePons et al, Ther Drug Monit 10: 421-7, 1988 : 

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

Maturation of Renal Function : 

Maturation of Renal Function fetal nephron development complete by 32wks gestational age at birth, renal function is related to gestational age rather than birth weight, length or body surface area the nephron matures after birth due to secretory load, regardless of GA

Proximal Tubular Function : 

Proximal Tubular Function rates of reabsorption of glucose, phosphate, bicarbonate and amino acids are lower (Fanconi’s profile) lower renal threshold for HCO3 and glucose serum phosphate increased due to transient hypoparathyroidism infants have higher serum phosphate than older child and adults serum calcium decreased

Distal Tubular Function : 

Distal Tubular Function acidification mechanisms intact can reduce urine pH to 4.8 and excrete acid load reduced ability to concentrate urine maximally but can dilute immature handling of Na leads to inc. secretion, prolonged in premature babies

Urine Output : 

Urine Output 30% of babies void at birth or soon after 92% in 24h, 99% in 48h in first 2 days 15cc/kg/ day oliguria <1cc/kg/h can also be polyuric- wt. loss>10%-DI

GFR and Creatinine : 

GFR and Creatinine GFR quite low at birth and then slowly increases reaches adult levels (corr. to 1.73 m2) by 12-18 mos. Creatinine higher the more premature the baby & take longer to stabilize Creatinine values reflect maternal levels for first few days

Chen et al, Pediatr Nephrol (2006) 21: 160-168 : 

Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 1 : 

Figure 1 Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 2 : 

Figure 2 Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 3 : 

Figure 3 Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 4 : 

Figure 4 Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 5 : 

Figure 5 Chen et al, Pediatr Nephrol (2006) 21: 160-168

Figure 6 : 

Figure 6 Chen et al, Pediatr Nephrol (2006) 21: 160-168

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. Hepatic Ontogeny

Cytochrome P450 (CYP) Enzymes : 

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 CYP3A4 Family (>40%) Subfamily (>55%) Isoform

Cytochrome P450 Enzymes : 

Cytochrome P450 Enzymes

CYP3A Ontogeny LaCroix D et al. Eur J Biochem 247:625, 1997 : 

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

Theophylline Urinary Metabolites : 

Theophylline Urinary Metabolites % Recovered in Urine Post-conception Age Age Range

Acetaminophen MetabolismMiller et al., Clin Pharmacol Ther 19:284-94, 1976 : 

Acetaminophen MetabolismMiller et al., Clin Pharmacol Ther 19:284-94, 1976 % of Dose

Pregnancy – Fetal Exposure : 

Pregnancy – Fetal Exposure Therapeutic Steroids with congenital adrenal hyperplasia Maternal Medications that can’t stop Thyroxine Immunosuppressants CNIs, steroids, azathioprine OK MMF stopped Inadvertent Exposures Eg. ACE inhibitors, ARBs etc Lifestyle & Recreational Drugs Cocaine, amphetamines, etc Disasters thalidomide

Bisphosphonate Use in Pediatric Patients : 

Bisphosphonate Use in Pediatric Patients An example of novel therapy and opportunity for investigation

Case Presentation # 1 : 

Case Presentation # 1 J.L. >> Dec 1995; age 13.05 yr Multiple Relapsing Nephrotic # 14 Previous cyclophosphamide & chlorambucil Biopsies x 3 >> MCD Fell out of bed T6,10, 12 Compression # (? New vs Old) Initial BMD z score = - 2.25

Corticosteroid-induced bone lossnonpharmacological approaches : 

Corticosteroid-induced bone lossnonpharmacological approaches lowest corticosteroid dose possible alternative steroid delivery eg. inhaled steroids exercise reduction of risk of falling

Corticosteroid-induced bone losspharmacological approaches : 

Corticosteroid-induced bone losspharmacological approaches HRT Calcium and Vit D Calcitonin Bisphosphonates

Bisphosphonate Pharmacology : 

Bisphosphonate Pharmacology Poor oral availability Short t1/2 (1-3 hrs) in serum Long t1/2 (years) in bone 50% renal excreted 50% bone absorbed

Slide 42: 

*Adults given pamidronate 1 mg/kg/dose typically achieve peak pamidronate levels of 2 – 3 mg/l

Idiopathic Hypercalcemia of Infancy : 

Idiopathic Hypercalcemia of Infancy 9 mon ? with FTT, developmental delay, dehydration, vomiting, constipation (not Williams’s Syndrome) Ca = 3.75 mmol/l (normal 2-1 -2-7) PTH undetectable 25 hydroxy vit D = 497 nmol/l (normal 125-250) 1,25 dihydroxy vit D = 94 pmol/l (normal 40-140) Hypercalciuria and nephrocalcinosis Osteocalcin reduced

Slide 45: 

Pamidronate 1 mg/kg/dose IV

Radiographs after pamidronate therapy Idiopathic Hypercalcemia of Infancy - age 2.37 years : 

Radiographs after pamidronate therapy Idiopathic Hypercalcemia of Infancy - age 2.37 years Pamidronate given at 0.79, 0.85, 0.90, and 1.01 yr Pamidronate given at 1.89, 2.06, 2.21, and 2.26 yr

Cyclosporin A Distribution in Brain, Liver, and Kidneys of Developing Mice: Implications for Risk of Neurotoxicity and Nephrotoxicity : 

Cyclosporin A Distribution in Brain, Liver, and Kidneys of Developing Mice: Implications for Risk of Neurotoxicity and Nephrotoxicity Goralski KB, Acott PD, Fraser AD, Worth D, Sinal CJ: Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression. Drug Metab Dispos. 2006 Feb;34(2):288-95.

Pediatric Clinical Problem : 

Pediatric Clinical Problem Pediatric Renal transplantation is treatment of choice for children with end-stage renal failure Seizures are common (17%) in first month post renal transplant More common in younger children

Background and Hypothesis : 

Background and Hypothesis Drug interactions in pediatric renal transplant patients can precipitate central nervous system (CNS) toxicity, behavioral disturbances and interruptions in immunosuppressive therapy. Nephrotoxicity is commonly associated with CNIs. P-glycoprotein (P-gp) encoded by the gene ABCB1 (MDR1) in humans and abcb1a (mdr1a) and abcb1b (mdr1b) in mouse and rat is expressed normally in epithelial cells of several organs including the brain, liver, intestine and kidney. The ABCB1 transporters play a key role in the absorption, elimination and tissue distribution of the primary immunosuppressants (CyA, tacrolimus and methylprednisolone) used in solid organ transplant Circumstances that impair P-gp-mediated drug transport may lead to decreased elimination, or altered entry of immunosuppressant drugs into the CNS. We hypothesize that neonatal and developing mice with less expression of mdr1a will be less protected against CyA accumulation in the brain. The increased drug accumulation could then have implications for nephrotoxixity and adverse CNS drug effects in infants or children post organ transplant.

Drug metabolism and distribution in neonates and children : 

Drug metabolism and distribution in neonates and children Drugs are handled differently by children than in adults Absorption, pH, gastric emptying Drug Metabolism cytochrome P450s Renal function: filtration and secretion Drug efficacy/toxicity

Role of MDR1 in CyA Kinetics : 

Role of MDR1 in CyA Kinetics MDR1 MDR1 MDR1 CYP3A MDR1 CYP3A Fecal elimination Oral CyA Intestinal Enterocytes Liver Hepatocyte Blood-Brain Barrier Kidney Proximal Tubules Systemic Circulation Portal Circulation Bile Elimination Urinary Elimination

Methods : 

Methods Effect of age and gender on mdr expression: Mdr1a and mdr1b expression in brain, liver and kidney was determined in 1 day, 12 day, 19 day and 6 week old male and female mice by quantitative PCR. Expression of the transporters was normalized to the tissue expression of the gene ribosome polymerase II. Effect of age and gender on CyA disposition: 1 day, 12 day, 19 day and 6 week old male and female Mdr1a-expressing and mdr1a knockout mice were administered i.v. Sandimune? (CyA) 5 mg/kg by i.p. injection. Whole blood and tissues were collected two hours later (c2) for CyA determination by HPLC-Mass Spec analysis.

Mdr1a -/- phenotype : 

Mdr1a -/- phenotype

HPLC-MS analysis of blood and tissue CyA levels : 

HPLC-MS analysis of blood and tissue CyA levels

mdr1a prevents CyA accumulation in the brain : 

mdr1a prevents CyA accumulation in the brain

Brain mdr1a expression is lower in young vs. adult mice : 

Brain mdr1a expression is lower in young vs. adult mice

Kidney and Liver mdr1a expression is lower in young vs. adult mice : 

Kidney and Liver mdr1a expression is lower in young vs. adult mice Kidney Liver

CyA levels are higherin brains of young vs. adult mice : 

CyA levels are higherin brains of young vs. adult mice

Summary : 

Summary Mdr1 expression was developmentally regulated. Newborns and developing mice had reduced levels of mdr1a expression in the brain, liver and kidney as compared to the adult mice. The effects of maturation were dependent on the transcript (mdr1a versus mdr1b), tissue and gender. Mdr1a was the primary transcript produced in the brain and liver. CyA kinetics in mouse mimic the kinetics of that drug in humans. Peak blood CyA (1200 ng/ml) was obtained 2 hr after i.p. dosing. At C2, CyA accumulated in the liver (8-12 fold) and kidney (4-8 fold). CyA accumulation within those organs was dependent on age but not dependent on gender or mdr1a expression. Neonatal and 12 day-old mdr1a+/+ mice had increased brain uptake of CyA as compared to adult mice. Conversely, neonatal and adult mdr1a-/- mice had similar brain accumulation of CyA. The renal concentration effect of CyA was most pronounced in 12 day and 19 day mice which may have implications to risk of CNI associated nephrotoxicity.

Children’s issues : 

Children’s issues Developmental pharmacology Weight or SA-based dosing Additional calculations Prescribing Dispensing Administration Double check calculations

Pediatric Administration Issues : 

Pediatric Administration Issues Dispensing errors Limited range of suitable formulations Doses ranges 0.1 mL – 10 mL Fractions of tablets Measuring small volumes Hundredths of a mL confused with tenths 0.03mL intended measured as 0.3ml Prepare difficult doses in Pharmacy

Physician Orders : 

Physician Orders Poor handwriting, decimal points and calculation errors 10x; 100x; 1000x digoxin; opiates Measured from single dose unit *** Prescriptions to include Age and weight mg/kg/dose All to demonstrate competence Charts/programs to aid calculation Leading (?) and trailing (?) zeros

Children’s issues : 

Children’s issues Intravenous infusions Dose for weight Rate of administration Prescribe Drug; Concentration Dose/kg/time Actual dose/time Route Rate per unit time Standardise Concentrations Diluents Infusion rate charts/programs

High risk medicines and procedures : 

High risk medicines and procedures Narcotics Cancer chemotherapy Oral methotrexate Anticoagulants Insulin Injectable cardiovascular drugs Patient identification Allergy status Correct administration route Dose calculations Preparation of IVs Use of IV infusion pumps

Conclusions : 

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 drugs in infants are needed Tissue sensitivity to the toxic effects of drugs may be age-dependent