Developmental Pharmacology - NIH Clinical Center - America's 发育药理学NIH临床中心-美国

1、Developmental PharmacologyScaling 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.Frank Balis, M.D.February 22, 2007ChloramphenicolNatural product of Streptomyces (1947)Inhibits protein sy

2、nthesis (bacteriostatic)Eliminated by glucuronide conjugation (90%) and renal excretion (10%)Nursery infections treated with high dosesO2NNClClOOHHHOHChloramphenicol in Infants3320 gm infant, 44 week gestationMeconium stained, foul smelling, timing of ROM unknownProcaine penicillin (50,00 units) + c

3、hloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hrDay 4, gray color & cold, moist skinDied at 106 hr, 8 hr after onset of vascular collapseSutherland, Am J Dis Child 97:761-7, 1959Chloramphenicol in Premature InfantsBurns et al., NEJM 261:1318-21, 1959Premature infants born 24 hrs after ROMGray

4、Baby Syndrome% of InfantsJaundiceVomitingAnorexiaResp. distressAbd. distentionCyanosisGreen stoolsLethargyAshen colorDeath45Burns et al., NEJM 261:1318-21, 1959Chloramphenicol Blood LevelsDay of LifeTotal Nitro Compounds g/mlTherapeutic rangeChloramphenicol dosesBurns et al., NEJM 261:1318-21, 1959C

5、hloramphenicol PharmacokineticsWeiss et al., NEJM 262:787-94, 1960Time hrTotal Nitro Compounds g/ml4-5 yrs. (n=3)1-2 days (n=5)10-16 days (n=3)t1/2 - 26 hrst1/2 - 4 hrst1/2 - 10 hrsRepeated AdministrationWeiss et al., NEJM 262:787-94, 1960Day of LifeTotal Nitro Compounds g/mlDrug Use in Infants and

6、ChildrenScaling 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 of developmental changes are often discovered when unexpected or severe toxicity in infants and children leads to

7、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).ZidovudineSynthetic nucleoside analogInhibits HIV reverse transcriptaseEliminated by gluc

8、uronide conjugation (67%) and renal excretion (33%)Perinatal therapy to prevent HIV transmissionZidovudine in the NewbornAge weeksZDV AUC ghr/mlBoucher et al., J Pediatr 122:137-44, 1993Zidovudine in NewbornsBoucher et al., J Pediatr 125:642-9, 1994Mirochnick et al., Antimicrob Agents Chemother 42:8

9、08-12, 1998Balis et al., J Pediatr 114:880-4, 1989Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987Prevention of HIV TransmissionHemoglobin g/dlAge weeksZidovudinePlaceboConnor et al., NEJM 331:1173-80, 1994Ontogeny and PharmacologyExcretory organ (liver and kidneys) development has the greatest

10、impact on drug disposition (pharmacokinetics)The most dramatic changes occur during the first days to months of lifeAnticipate age-related differences in drug disposition based on knowledge of ontogenyEffect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamics) is poorly studiedDisease

11、 states may alter a drugs PK/PDGlomerular filtration rateLow at birthFull term newborn - 10-15 ml/min/m2Premature - 5-10 ml/min/m2GFR doubles by 1 week of ageAdult values by 6-12 months of ageTubular functionSecretory function impaired at birthGlomerulotubular imbalanceAdult values by 1 year of ageR

12、enal OntogenyGlomerular Filtration RateGFR ml/min/1.73 m2Age monthsAperia, Acta Pdiatr Scand 64:393-8, 1975GFR in InfantsGFR ml/min/1.73 m2Age daysGuignard, J Pediatr 87:268-72, 1975Gentamicin in the NewbornGentamicin Clearance ml/kghrCreatinine Clearance ml/kghr15 full term23 prematureKoren et al.,

13、 Clin Pharmacol Ther 38:680-5, 1985Gentamicin ClearancePostnatal AgeGentamicin Clearance L/kghrPremature (40%)Subfamily (55%)IsoformCYP OntogenyKearns GL et al. NEJM 349: 1157, 2003CYP2E1 OntogenyCYP3A Ontogeny30w1yrAdultFetusPostnatal AgeCYP3A7 ActivityCYP3A4 ActivityLaCroix D et al. Eur J Biochem

14、247:625, 19970.30.751.61.8G:SAcetaminophen MetabolismMiller et al., Clin Pharmacol Ther 19:284-94, 19760.150.170.190.18kel% of DoseTheophylline Urinary Metabolites% Recovered in UrinePost-conception AgeAge RangeClearance ml/min/kg2070100Factors Affecting Drug DistributionPhysicochemical properties o

15、f the drugCardiac output/Regional blood flowDegree of protein/tissue bindingBody compositionExtracellular waterAdipose tissueOntogeny of Body Composition% of Total Body WeightEC H2OIC H2OProteinOtherFatKaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992Volume of Distribution of Sul

16、faVolume of Distribution L/kgRoutledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994Tissue and Organ WeightPlasma ProteinsProtein Binding in Cord and Adult PlasmaKurz et al., Europ J Clin Pharmacol II:463-7, 197730.217.3CSF MTX and AgeTime daysCSF Methotrexate MBleyer, Cancer Treat Rep 61:1419-25,

17、1977CNS Growth and DevelopmentAge yrsAdult Value %CNS VolumeBody Surface AreaBleyer, Cancer Treat Rep 61:1419-25, 1977Adaptive IT MTX Dosing RegimenBleyer, Cancer Treat Rep 61:1419-25, 1977Dose Change with Adaptive RegimenAge yrs% Change in DoseAdaptive dose12 mg/m2 doseX 100Bleyer, J Clin Oncol 1:3

18、17-25, 1983Effect of Adaptive IT Dosing on OutcomeIncidence ofCNS Relapse%MTX Dose Based on BSAMTX Dose Based on AgeAge monthsConcurrentIsolated0100102012 YrAdultATRAMTD60 mg/m2/d90 mg/m2/d150 mg/m2/dDLTPseudotumor cerebriHA and PCDermatologic9-cis-RAMTD35 mg/m2/d85 mg/m2/d140 mg/m2/dDLTPseudotumor cerebriHA and PCHA, diarrhea, dermatologicConclusionsInfa