Use of drugs in children with impaired renal function: what is to worry about? Augustina Jankauskienė, Vilnius university children hospital, Lithuania.

Use of drugs in children with Use of drugs in children with impaired renal function: what impaired renal function: what

is to worry about?is to worry about?

Augustina JankauskienAugustina Jankauskienėė,,

Vilnius university children hospital, Vilnius university children hospital, LithuaniaLithuania

Dosing information for pediatric Dosing information for pediatric patients: are they really patients: are they really “therapeutic orphans”?“therapeutic orphans”?

Inadequate pediatric dosing informationInadequate pediatric dosing informationss from 1497 from 1497 sources were sources were rewieved:rewieved:

< 1 month (80.5%)< 1 month (80.5%) 1-3 months1-3 months (79.1%)(79.1%) 33 months- 2 years (77.5%)months- 2 years (77.5%) 2-6 years (73.2%)2-6 years (73.2%) 6 -12 years (71.6%)6 -12 years (71.6%) Tan E, Med J Austr, 2003, 179(4):195-8Tan E, Med J Austr, 2003, 179(4):195-8

Cochrane reviewsCochrane reviews

Using “Using “chronic renal failurechronic renal failure”” in the Title, in the Title, Abstract or Keyword and Abstract or Keyword and ““drug therapydrug therapy”” in the Title, Abstract or Keyword and in the Title, Abstract or Keyword and ““childrenchildren”” in abstract in in abstract in ““Cochrane Cochrane database of Systematic Reviews” there database of Systematic Reviews” there were 12 results out of 5416were 12 results out of 5416

There isThere is the the reason to worry:reason to worry:

Most studies on drug dosage are Most studies on drug dosage are performed performed oon adultsn adults

Two thirds of all drugs used in clinical Two thirds of all drugs used in clinical practipracticce are totally or partially excreted by e are totally or partially excreted by the kidneythe kidney

Off-label use is commonOff-label use is common Requires multiple considerations, is time Requires multiple considerations, is time

consuming and error-prone consuming and error-prone

Approach to pediatric drug dosing Approach to pediatric drug dosing Physiological characteristics of the child:Physiological characteristics of the child:

AAbsorptive capacity (reaches adult values at 2 years of bsorptive capacity (reaches adult values at 2 years of age)age)

Gastric emptGastric emptyying delayed, approaches adult values ing delayed, approaches adult values within 6-8 monthswithin 6-8 months

Intramuscular administration of the drugs is unreliable in Intramuscular administration of the drugs is unreliable in neonates since blood flow to the muscles varies over neonates since blood flow to the muscles varies over the first 2-3 wthe first 2-3 weekseeks

Percutaneous absorption can be faster and higherPercutaneous absorption can be faster and higher

Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-10972006:45(11):1077-1097

Approach to pediatric drug dosing Approach to pediatric drug dosing Pharmacokinetic parameters of the drugPharmacokinetic parameters of the drug

Bioavailability of the drug and frequent feedingBioavailability of the drug and frequent feeding Bioavailability of a rectal solution of paracetamol Bioavailability of a rectal solution of paracetamol

in infants was shown to be decreased in in infants was shown to be decreased in comparison to suppository formulationscomparison to suppository formulations

Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-1097Pharmacokin 2006:45(11):1077-1097

Goals and limitations of Goals and limitations of pharmacologypharmacology

Level of active component in the target Level of active component in the target organorgan

Preexisting renal diseasePreexisting renal disease Variation of body compositionVariation of body composition Diet as a function of age Diet as a function of age

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

In patients with chronic kidney disease, over-the-counter and herbal medicine C 17, 21, 25,

use should be assessed to ensure that medications are indicated; medications 30, 36, 43

with toxic metabolites should be avoided, the least nephrotoxic agents should be used, and alternative medications should be used if potential drug interactions exist.

Physicians should be aware of drugs with active metabolites that can C 25

exaggerate pharmacologic effects in patients with renal impairment.

Dosages of drugs cleared renally should be adjusted based on the C 1, 4

patient’s renal function (calculated as creatinine clearance or glomerular filtration rate); initial dosages should be determined using published guidelines and adjusted based on patient response; serum drug concentrations should be used to monitor effectiveness and toxicity when appropriate.

C = consensus, disease oriented evidence, usual practice, expert opinion, or case series.

REFERENCES: 1.National Kidney Foundation. K/DOQI clinical practice guidelines for chronic idney disease: evaluation, classification, and stratification. Am

J Kidney Dis 2002;39 (2 suppl 1):S1-266.4. Aronoff GR. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 4th ed. Philadelphia, Pa.: American College of Physicians,

1999.17.Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. CMAJ 2002;166:473-7.21.Livornese LL Jr, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure. Infect Dis Clin North Am 2004;18:551-

79.25.Drayer DE. Pharmacologically active drug metabolites: therapeutic and toxic activities, plasma and urine data in man, accumulation in

renal failure. Clin Pharmacokinet 1976;1:426-43.30. Bennett WM, Henrich WL, Stoff JS. The renal effects of nonsteroidal anti-inflammatory drugs: summary and recommendations. Am J

Kidney Dis 1996;28 (1 suppl 1):S56-62.36. Gambaro G, Perazella MA. Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase

inhibitors. J Intern Med 2003;253:643-52.43. Isnard Bagnis C, Deray G, Baumelou A, Le Quintrec M, Vanherweghem JL. Herbs and the kidney. Am J Kidney Dis 2004;44:1-11.

Factors influencing drug dosageFactors influencing drug dosage

AgeAge Specific drugsSpecific drugs Combination of drugsCombination of drugs PharmacogeneticsPharmacogenetics Underlying diseaseUnderlying disease The dosage of toxinsThe dosage of toxins Concomitant medicationsConcomitant medications DehydrationDehydration

Table: Classification of various drugs based on pathophysiologic categories of acute kidney injury

Pathophysiology Drugs known to cause acute kidney injury

Prerenal failure NSAIDs, ACE inhibitors, cyclosporine A (CyA), norepinephrine, AT2-receptor antagonists, diuretics, interleukins, cocaine, mitomycin C, tacrolimus, estrogen, quinine

Acute tubular necrosis

Antibiotics: aminoglycosides, cephalosporins, amphotericin B, rifampicin, vancomycin, foscarnet, pentamidineNSAIDs, glaphemin, contrast media, acetaminophen, CyA, cisplatinum, i.v. immunoglobulin, dextran, maltose, sucrose, mannitol, heavy metals

Acute interstitial nephritis

Antibiotics: ciprofloxacin, methicillin, penicillin G, ampicillin, cephalosporins, oxacillin, rifampicin NSAIDs, glaphenin, acetylsalicylic acid (ASA), fenoprofen, naproxen, phenylbutazone, piroxicam, tolmetin, zomepirac, contrast media, sulfonamides, thiazides, phenytoin, furosemide, allopurinol, cimetidine, omeprazole, phenindione

Tubular obstruction Sulfonamides, methotrexate, methoxyflurane, glaphenin, triamterene, acyclovir, ethylene glycol, protease inhibitors

Hypersensitivity angiitis

Penicillin G, ampicillin, sulfonamides

Trombotic microangiopathy

Mitomycin C, CyA, oral contraceptives

deBroe ME et all (2003) Clinical nephrotoxins: Renal injury from drugs and chemicals, 2 edn.Kluwer Academic, Dordrecht

Dose adjustmentDose adjustment

Body weight-based dosing regimentsBody weight-based dosing regiments Body surface area (BSA)Body surface area (BSA) based dosing based dosing

regimentsregiments Age based dosing regimentsAge based dosing regiments Physiological parameters:Physiological parameters: cardiac output, cardiac output,

extracellular water volume,extracellular water volume, resting resting metabolic ratemetabolic rate

Protein binding characteristicsProtein binding characteristics

Dosage guideline based on renal excretion. From: Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-10971097

AS – Active Tubular Secretion. A marker for AS is p-aminohippuric acid

Several basic principlesSeveral basic principles

Accumulation of drugs and their metabolitesAccumulation of drugs and their metabolites Modification of drug doses necessary when Modification of drug doses necessary when

GFR< 30 – 40 ml/min/ 1.73mGFR< 30 – 40 ml/min/ 1.73m²² Dosing intervalDosing interval Reducing the size of individual dosageReducing the size of individual dosage Loading doseLoading dose Drug monitoringDrug monitoring

Daschner M, Ped Nephrol(2005)20:1675-1686 Daschner M, Ped Nephrol(2005)20:1675-1686

Trompeter RS, Ped Nephrol, 1987, 1: 183 - 194Trompeter RS, Ped Nephrol, 1987, 1: 183 - 194

Table: Drug doses for children with normal and reduced kidney function. All doses are given for normal renal function, for a glomerular filtration rate (GFR) of 40 and 10 ml/min/1,73 m2, and for anuric patients. The doses for reduced renal function are calculated as a percentage of the normal dose and divided into the indicated number of single doses (for example: normal dose 100 mg/ kg/day in two single doses = 2 x 50 mg/kg daily; dose at a GFR of 10 ml/min/1,73 m2: 30 % in one single dose = 1 x 30 mg/kg daily)Daschner M. Pediatr Nephrol (2005)20: 1675-1686

Group/ subgroup Normal daily dose, number of single doses

Dose at GFR (ml/min/1.73m2) Dialysis

40 10 Anuric

Aldosterone antagonists

Spironolactone PO: 1-5 mg/kg in 2 single dosesIV: -5mg/kg in 4 single doses

50 %(1 single dose)

25 %(1 single dose)

Contraindicated

Analgesics/ anti-inflammatory agents

Acetylsalicylic acid 5(-10) mg/kg as single dose (max. 4x/day)

75 % 50 % (increasedose interval)

50 % (increasedose interval)

Ibuprofen 20-30 mg/kg in 3-4 single doses Max. daily dose 1.2 g

Normal dose Normal dose Normal dose

Paracetamol 10-20 mg/kg as single dose(max.4x/day). Max. daily dose 4g

Normal dose 50 % (increasedose interval)

50 % increasedose interval)

Antibiotics aminoglycosides

Gentamicin 3-5 mg/kg/day in 3 single doses Peak level 5-10 mg/ml Trough level 0.5-2 mg/lMax. daily dose 360 mg

60 % (2 singledoses) Reduceloading dose

10 % (1 singledoses) Reduceloading dose

5 % (1 single dose), loading dose 1-2 mg/kg

15 % after hemodialysis;Intraperitonea loadingdose 8 mg/l,Maintenance dose 4mg/l

Antivirals

Ganciclovir IV: initial (14 days) 10 mg/kg/dayin 2 single doses, then 5mg/kg/day in 1 singlePO: 100 mg/kg/day in 3 single dosesPO dose at GFR < 40: mg/kg =GFR; max. daily dose 3g PO

IV: 40 % (2 single doses)

10 % (1 singledose); orally in

2single doses

1.25mg.kg afterEachhemodialysis(or5 % duringPeritonealdialysis); PO in2 single doses

1.25 mg/kg after each Hemodialysis(or 5 % duringPeritoneal dialysis); PO in 2 single doses

Too complicated for crude Too complicated for crude guidelines guidelines

Avoid unfamiliar drugsAvoid unfamiliar drugs Systematically check the recommended Systematically check the recommended

dosage in tablesdosage in tables Check plasma drug levelCheck plasma drug level Delete any non-essential treatmentDelete any non-essential treatment Assess renal function during the entire Assess renal function during the entire

duration of treatment duration of treatment

RecommendationsRecommendations

For preventing For preventing amphotericinamphotericin-induced -induced nephrotoxicity: saline infusion prior to nephrotoxicity: saline infusion prior to administration (10 – 15 ml/kg body weigh) administration (10 – 15 ml/kg body weigh) and use of lipid formulations of and use of lipid formulations of amphotericinamphotericin

Goldman RD, Koren G. J Pediatr Hematol Oncol (2004)26:421 -426Goldman RD, Koren G. J Pediatr Hematol Oncol (2004)26:421 -426, ,

RecommendationsRecommendations

Radiocontrast mediaRadiocontrast media: preventive : preventive measures: intravenous hydration and measures: intravenous hydration and administration of acetylcysteine administration of acetylcysteine

Tepel M, Zidek W (2004). Curr Opin Nephrol Hypertens13: 649-654Tepel M, Zidek W (2004). Curr Opin Nephrol Hypertens13: 649-654

CytostaticsCytostatics: infusion of mannitol and : infusion of mannitol and salinesaline

Liposomal formulation of cisplatin, Liposomal formulation of cisplatin, LipoplatinLipoplatin

Recommended readingRecommended reading

Daschner M (2003) Tabelarium Daschner M (2003) Tabelarium Nephrologicum. Shaker Verlag, AachenNephrologicum. Shaker Verlag, Aachen

Daschner M, Ped Nephrol (2005) 20:1675-1686Daschner M, Ped Nephrol (2005) 20:1675-1686

Resources for More Information About Dosing Adjustments in Patients with Chronic Kidney Disease

Drug Prescribing in Renal Failure: Dosing Guidelines for Adults

Publisher: American College of Physicians PDA download: http://acp.pdaorder.com/pdaorder/-/605920537541/ item?oec-catalog-item-id=1028

FDA Center for Food Safety and Applied Nutrition Web site: http://www.cfsan.fda.gov/

FDA MedWatch Web site: http://www.fda.gov/medwatch/index.html

Medline Plus (herbal medicine) Web site: http://www.nlm.nih.gov/medlineplus/herbalmedicine.html

National Center for Complementary and Alternative Medicine Web site: http://www.nccam.nih.gov/

National Kidney Disease Education Program Web site: http://www.nkdep.nih.gov

National Kidney Foundation Web site: http://www.kidney.org/

Guidelines must run the Guidelines must run the gaungaunttlet between being too let between being too general to be useful and too general to be useful and too

specific to be exclspecific to be excluusivesiveBaber N.S. Paediatric regulatory Baber N.S. Paediatric regulatory

guidelines: do they help in optimising guidelines: do they help in optimising dose selection for children?dose selection for children?Br J Clin Pharmacol, Br J Clin Pharmacol, 22000055