한국임상약학회지제 27 권제 2 호 Korean J Clin Pharm, Vol. 27, No. 2, 2017 Review Article Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy pissn 1226-6051 eissn 2508-786X https://doi.org/10.24304/kjcp.2017.27.2.63 Korean journal of clinical pharmacy (Online) URL: http://www.ekjcp.org 신생아중환자의약동학적다양성에영향을미치는요인 안숙희 * 원광대학교약학대학 (2017년 6월 27일접수 2017년 6월 28일수정 2017년 6월 28일승인 ) Contributing Factors on Pharmacokinetic Variability in Critically Ill Neonates Sook Hee An* College of Pharmacy, Wonkwang University, Jeonbuk 54538, Republic of Korea (Received June 27, 2017 Revised June 28, 2017 Accepted June 28, 2017) ABSTRACT Neonates have large inter-individual variability in pharmacokinetic parameters of many drugs due to developmental differences. The aim of this study was to investigate the factors affecting the pharmacokinetic parameters of drugs, which are commonly used in critically ill neonates. Factors that reflect physiologic maturation such as gestational age, postnatal age, postconceptional age, birth weight, and current body weight were correlated with pharmacokinetic parameters in neonates, especially preterm infants. Comorbidity characteristics affecting pharmacokinetics in critically ill neonates were perinatal asphyxia, hypoxic ischemic encephalopathy, patent ductus arteriosus (PDA), and renal dysfunction. Administration of indomethacin or ibuprofen in neonates with PDA was associated with the reduced clearance of renally excreted drugs such as vancomycin and amikacin. Therapeutic hypothermia and extracoporeal membrane oxygenation were influencing factors on pharmacokinetic parameters in critically ill neonates. Dosing adjustment and careful monitoring according to the factors affecting pharmacokinetic variability is required for safe and effective pharmacotherapy in neonatal intensive care unit. KEY WORDS: Neonates, neonatal intensive care unit, pharmacokinetics, preterm infants 신생아는각종장기와효소의기능이미숙하고, 성장과발달이이루어지는시기이다. 따라서신생아는성인과다른약동학적특성을지닌다. 체내총수분량은성인에비해증가하고지방의양은감소하며약물의단백결합이감소하여약물의분포가변화한다. 1-2) 또한간혈류와간대사효소의활성, 신장배설의차이로인하여약물의청소율 (clearance) 에변화가나타난다. 2-4) 신생아에서약물의분포용적, 반감기, 청소율등은소아나성인과다른범위를나타내며, 개체간의차이가크게나타난다. 5-8) 이러한신생아의약물동태학적특성을바탕으로한용량의설정및모니터링은안전하고효과적인약물사용을위해필수적이다. 신생아중환자실에서주로사용되는 aminophylline (theophylline), phenobarbital, gentamicin, amikacin, vancomycin등의약물은환자개인간의약물동태학적특성이다양하여약물혈중농도모니터링 (therapeutic drug monitoring, TDM) 서비스를통하여용량 을조정하고있다. 신생아경련의일차치료약물로사용되는 phenobarbital의약동학연구결과를보면, 분포용적의평균이 0.69-1.89 L/kg, 반감기는 17-177시간, 청소율이 0.004-0.009 L/ kg/hr로보고되어개체간의차이가크게나타났다. 9-19 미숙아무호흡의예방과치료에사용되는 theophylline의연구에서도약동학파라미터들의평균치가각각분포용적이 0.33-1.89 L/ kg, 반감기가 15-34시간, 청소율이 0.013-0.039 L/kg/hr로개체간의차이가크게나타났다. 20-27) 따라서이러한다양성에영향을주는요인을파악하여약물의용량과투여간격을설정해야한다. 신생아중환자실에서사용하는 TDM대상약물의초기용량지침은 Neofax나 Pediatric dosage handbook과같은문헌을참고하여사용하고있으나, 5,28) 초기용량을투여하고약물의혈중농도를측정하였을때치료혈중농도를벗어나는경우가종종발생한다. 이는신생아의다양한임상특성과성장에따 *Correspondence to: Sook Hee An, College of Pharmacy, Wonkwang University, 460 Iksan daero, Iksan, Jeonbuk 54538, Republic of Korea Tel: +82-63-850-6821; Fax: +82-63-850-7309 E-mail: shan7@wku.ac.kr 63
64 / Korean J Clin Pharm, Vol. 27, No. 2, 2017 른약동학적변화가충분히반영되지않았기때문인것으로사료된다. 본종설에서는신생아에게주로사용되는약물의약동학파라미터에영향을주는요인에대하여신생아의성숙 (maturation) 정도를반영하는특성인자, 장기의기능, 공존질환과치료요법, 병용약물등의관점에서고찰하여신생아에게적절한약물의용량과모니터링지침의설정에도움이되고자한다. 본 신생아특성인자신생아중환자실에입원하여약물치료를받게되는신생아는재태연령 (gestational age, GA) 이 37주미만인미숙아가대부분이며, 미숙아는출생체중이 2.5 kg 미만인저출생체중아 (low birth weight infant), 체중이 1.5 kg 미만인극소저출생체중아 (very low birth weight infant), 출생체중이 1kg 미만인초극소저출생체중아 (extremely low birth weight infant) 로분류한다. 신생아의자궁내성장 (intrauterine growth) 정도를반영하는 GA와출생체중이약물의분포용적및청소율과밀접한관련이있다. 신생아의조기패혈증 (early onset sepsis) 치료에사용되는 gentamicin의분포용적은 GA가작을수록크게나타나는데, GA가 30주미만인미숙아의분포용적은 0.7 L/kg이나, GA가 37주이상인만삭아의분포용적은약 0.5 L/kg 정도이다. 29) 이는신생아의 GA가작을수록체내총수분량이증가하여수용성약물의분포용적이증가하기때문이다. 또한, GA와체중이작을수록 gentamicin의반감기가연장되고청소율이감소하게되는데, 이는사구체여과율 (glomerular filtration rate, GFR) 과관련이있다. 29-30) 따라서 gentamicin의용량지침은대부분신생아의 GA에따라용량과투여간격을세분화하여제시하고있다. 5,28) 신생아의출생후나이 (postnatal age, PNA) 와수태후연령 (postconceptional age, PCA) 도약물의반감기와청소율에영향을주는인자이다. 이는 PNA와 PCA의증가에따른대사와배설기능의성숙에의한것으로추정된다. 2) 한국신생아를대상으로한 amikacin의약동학연구에서 PNA와 PCA가 amikacin의청소율에영향을미치는유의한인자였으며, 31) 서양인을대상으로한연구에서도비슷한결과를보여주었다. 32-34) Theophylline의약동학연구에서도대부분 PNA와 PCA가청소율에영향을미치는유의한인자로제시되었다. 20,21,27) 한국신생아를대상으로한집단약동학연구에서 theophylline의청소율에영향을미치는인자는 PNA와체중이었다. 20) Gentamicin의집단약동학연구에서도 GA, 체중과함께 PNA가청소율에영향을미치는유의한인자였다. 35) Phenobarbital에대한집단약동학연구에서도 PNA가청소율의예측인자로제시되었다. 12) Vancomycin의반감기는 PCA가작을수록연장되어있으며, PCA 27-30주에 6.6 ± 0.4시간, PCA 31-36주는 5.6 ± 0.4시간, 론 PCA가 37주이상인경우에 4.9±0.4시간으로보고되었다. 36) 부당경량아 (small for gestational age, SGA) 에해당하는경우에 gentamicin 의청소율이감소했다는보고가있는데, 재태연령이 32주미만이면서 SGA인환자들에서생후첫주에 gentamicin의평균청소율이 0.58 ml/kg/min 으로적정체중아 (appropriate for gestational age, AGA) 의평균치인 0.68 ml/kg/min 에비하여유의하게감소하였다. 37) 따라서신생아에서신배설과간대사의성숙정도를반영하는특성인자인 GA, 출생체중, PNA, PCA, 체중등에따른약동학적변화를잘파악하여용량을결정하는것이중요하다. 신기능신생아는성인에비해사구체여과, 세뇨관분비, 새뇨관재흡수의기능이감소되어있으므로신배설약물의청소율이감소하여체중당유지용량이더작게필요한경우가많다. 2) 만삭아의 GFR은 2-4 ml/min이며, 미숙아는 0.6-0.8 ml/min으로더욱감소되어있다. 38) 나이가증가함에따라신기능이성숙하며, 만삭아는출생후 1-2주동안 GFR이두배정도증가한다. 3) 미숙아는만삭아에비해 GFR의성숙이지연되는것으로알려져있으며, 특히 GA가 30주미만이거나극소저출생체중아인경우 GFR이더욱지연된다. 3) Vancomycin과같이사구체여과에의해주로배설되는약물의청소율은신기능과밀접한관련이있다. 39) 신기능을나타내는혈청크레아티닌농도 (serum creatinine, SCr) 와 vancomycin의청소율은음의상관관계가있음이많은연구에서보고되었다. 40-42) 신생아특성인자중 PCA가신생아의신기능을가장잘반영한다고보고하였고, 43) vancomycin의용량지침도 PCA나 SCr에따라제시하고있다. 36,44-46) Gentamicin이나 amikacin과같은 aminoglycosides도신장으로주로배설되는약물이므로신기능에따라청소율이변화한다. SCr과 GFR이 aminoglycosides 청소율의예측인자로제시되고있다. 34,47) 따라서환자의신기능을잘파악하여신배설약물의용량을결정하고, 신기능의변화에따른용량조절이필요하다. 주산기가사 (perinatal asphyxia) 주산기가사가있었던신생아는간장과신장으로의관류가감소하여약물의대사와배설이영향을받을수있다. 주산기가사가있었던환자에서 theophylline, phenobarbital, aminoglycosides 의청소율이감소했다는보고가있으므로 TDM을통한용량조절이필요하다. 48-51) 주산기가사환자에서 theophylline의청소율은 16.4 ± 5.3 ml/kg/hr로대조군의 20.2 ± 5.4 ml/kg/hr에비하여감소하였으며, 분포용적은차이가없었다. 48) 주산기가사가있었던환자는약물의용량을 50% 까지감량하는것이필요할수있다. 2)
신생아중환자의약동학적다양성에영향을미치는요인 / 65 저체온치료 (hypothermia) 저산소성허혈성뇌병증 (hypoxic ischemic encephalopathy, HIE) 의표준치료법으로사용되고있는저체온치료는심박출량감소, 혈관수축등의혈역학적변화를일으켜약물동태에영향을미칠수있다. 52) 저체온치료는조직관류를감소시키고, cytochrome P450 (CYP) 와 uridine diphosphate (UDP)- glucuronosyltransferase (UGT) 의활성을감소시킨다. 53) 출생초기에 HIE로저체온치료를받은환자에게사용빈도가높은약물은 gentamicin과 phenobarbital이다. Gentamicin의약동학연구에서는저체온치료를받은환자군의평균반감기가 9.16 시간으로저체온치료를받지않은환자군의평균반감기인 6.56시간에비해유의하게연장되었으며, 청소율도저체온치료를받은환자군은 0.04 ± 0.01 L/kg/hr로저체온치료를받지않은환자군의평균치인 0.05 ± 0.01 L/kg/hr에비하여낮게나타났다. 54) 또다른연구에서도저체온치료를받은환자군에서 gentamicin의청소율이 0.033 L/kg/hr로저체온치료를받지않은환자군의청소율인 0.051 L/kg/hr에비하여낮게나타났다. 55) 따라서이들연구에서는저체온치료를받는신생아에게 gentamicin의투여간격을 24시간에서 36시간으로연장할것을추천하고있다. Phenobarbital의약동학에대한저체온치료의영향은연구마다다른결과를보여주고있어아직결론을내리기어렵다. HIE로저체온치료를받은신생아에서 phenobarbital 의혈중농도가증가하고반감기가연장되었다는보고가있으나, 17) 또다른두개의집단약동학연구에서는저체온치료가 phenobarbital의청소율과분포용적에영향을주는요인이아니었다. 15-16) 최근신생아약동학에대한저체온치료의영향에관한연구가활발히진행되고있으며, morphine의청소율을감소시키고, ampicillin의분포용적을증가시키며청소율을감소시킨다는연구결과가발표되었다. 56-57) 저체온치료를받는환자는 HIE로인한간기능과신기능의저하를동반하는경우가많으므로약동학변화의요인이저체온치료자체에의한것인지 HIE에의한것인지명확하게구분하기어려울수있으나, HIE로저체온치료를받는환자에서약동학변화의가능성을인식하여용량조정을하는것은안전하고효과적인약물치료를위하여필수적이다. 체외막산소화장치 (extracorporeal membrane oxygenation) 체외막산소화장치 (extracorporeal membrane oxygenation, ECMO) 는심각한호흡부전과심부전환자에게심폐기능을대체하기위해사용된다. 58) 신생아에서 ECMO는선천성횡경막탈장 (congenital diaphragmatic hernia), 폐동맥고혈압 (pulmonary hypertention), 태변흡입 (meconium aspiration) 등으로인한호흡부전환자나선천성심장기형 (congenital cardiac defect) 으로인한수술후환자에게사용된다. 59) ECMO는약동학파라미터에영향을줄수있다고알려져있는데, 이는 ECMO가순환혈 액량을증가시키고일시적으로신장기능의변화를일으키기때문인것으로추정한다. 60-61) 신생아에서사용하는약물중 ECMO에의한영향이알려진약물로 gentamicin이있다. ECMO 를받은신생아에서 gentamicin의분포용적이증가하고, 반감기가연장되었으며, 청소율이감소하였다고보고되었다. 62-63) Gentamicin의분포용적은 ECMO를받은신생아에서 0.57-0.75 L/kg로 ECMO를받지않은환자의값인 0.45-0.47 L/kg에비해증가했다. 62-63) Gentamicin의반감기는 ECMO를받은신생아에서 9.2-10.7시간으로 ECMO를받지않은환자의값인 3.9-5.7시간에비해연장되었으며, 청소율은 ECMO를받은환자에서 0.24 L/hr으로 ECMO를받지않은환자의값인 0.35 L/hr 에비해감소하였다. 62-63) Vancomycin에관하여는연구마다다른결과를보여주고있는데, ECMO를받은신생아에서 vancomycin의분포용적과반감기가증가하고, 청소율이감소했다는연구도있고, 64) 분포용적과청소율에는변화가없고반감기만증가했다는연구도있다. 65) 이외에도 ECMO를투여받는신생아에서 midazolam, morphine, cefotaxime 등의약물의분포용적이증가했다는연구결과들이있다. 66-69) ECMO를받는환자에게진정목적으로사용되는 midazolam 과 morphine은 ECMO 치료가진행됨에따라환자의상태가회복되면서약물의청소율이증가하여충분한진정효과를보기위한용량증가의필요성이제시되고있다. 70) ECMO를받는환자는신기능과투석여부, 시간이지남에따른환자의회복여부등을고려하여약물용량을조절하고지속적으로모니터링하는것이필요하다. 동맥관개존증동맥관개존증 (patent ductus arteriosus, PDA) 이있는신생아에서 gentamicin의분포용적이증가하며, 동맥관이닫힌후에는분포용적이 30% 이상감소됨이보고되었다. 71-73) 그러나 PDA 가 gentamicin 의분포용적에영향을미치지않는다는보고도있다. 74) 병용약물 PDA의치료를위해투여하는 indomethacin과 ibuprofen은신혈류를감소시켜신배설약물의청소율을감소시킬수있다. PDA가있는미숙아에서 indomethacin의병용이 amikacin의최고혈중농도를 17%, 최저혈중농도를 28% 증가시켰다고보고되었다. 75) Indomethacin의병용은 vancomycin의청소율을 46% 감소시켰다. 76) PDA에사용되는 ibuprofen도 amikacin의청소율을 21% 감소시키며, vancomycin의청소율은 28% 감소시켰다. 76) 이러한약물상호작용으로인하여 PDA 치료를받는신생아에게신독성의위험이증가할수있으므로각별한모니터링이필요하다.
66 / Korean J Clin Pharm, Vol. 27, No. 2, 2017 Table 1. Factors influencing pharmacokinetics in critically ill neonates. Classification Physiologic maturation Renal function Comorbidity Therapy Concomitant medication Factors Gestational age, postnatal age, postconceptional age, birth weight, current body weight Serum creatinine, glomerular filtration rate Perinatal asphyxia, hypoxic-ischemic encephalopathy, patent ductus arteriosus, renal dysfunction Hypothermia, extracorporeal membrane oxygenation, dialysis Indomethacin, ibuprofen 유전적다형성성인에서는유전적다형성 (genetic polymorphism) 이약동학에미치는영향에관한연구가활발히이루어지고있으나, 아직신생아를대상으로한연구는많지않다. 한국미숙아를대상으로한연구에서 CYP1A2*1C와 CYP1A2*1F가 theophylline 의청소율에영향을미치지않는다는보고가있으며, 20) 신생아경련이있는한국신생아에서 CYP2C19의단일염기다형성 (single nucleotide polymorphism) 이 phenobarbital의약동학파라미터에영향을주지않는다는연구결과가있다. 14) 또한미숙아에서 UGT2B7의단일염기다형성이 morphine의약동학에영향을준다는보고가있었다. 77) 성인에서유전적변이에의한약동학의변화로약물의효과와부작용의빈도에영향을준다고알려진약물정보를신생아에게그대로적용할수없다. 신생아의약동학적다양성에영향을주는많은요인들 (Table 1) 과더불어유전적다형성에관한연구도앞으로개척해야할분야이다. 결 신생아중환자의약물동태에영향을미치는인자를파악하여이에따른용량조절과모니터링을하는것은안전하고효과적인약물치료에필수적이다. 신생아의재태연령과출생체중에따른약동학파라미터의차이와출생이후성장을반영하는 PNA, PCA, 체중의변화에따른약동학의변화를인지하고약물의용량을조정하는것이필요하다. 신기능이저하된환자에게는신배설약물의약동학변화가나타나므로감량이나투여간격의연장이필요하며, 신기능이회복된이후에이에따른재조정을놓치지않도록한다. 주산기가사와동맥관개존증과같은공존질환이약동학의변화를일으킬수있으며, 이러한질환의치료법과약물의사용도약동학에영향을줄수있다. 주산기가사로인한저산소성허혈성뇌병증에저체온치료를적용할때약물의청소율이감소하며, 동맥관개존증이있는환자에게 indomethacin이나 ibuprofen과같은약물의사용이신배설약물의청소율을감소시키고신독성을일으킬수있으므로이에따른용량조절과모니터링이필요하다. 체외막산소화장치의사용도약동학에영향을주므로용량설정에있어고려해야할요인이다. 또한신생아에서유전 론 적다형성에의한약동학연구가많지않으나, 이러한가능성을염두에두고이분야에대한연구가이루어져야하겠다. 신생아중환자의약물치료과정에서고려해야할약동학적변화요인을잘파악하여환자개개인에게적합한약물치료가이루어지길기대한다. 감사의말씀 본연구는한국연구재단의지원을받아수행되었으며 ( 과제번호 : NRF-2015R1D1A1A01057223), 자료정리를도와준원광대학교약학과임상약학연구실의이소연, 박정호, 최동욱학생에게감사의마음을전합니다. 참고문헌 1. Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta Peadiatr Scand Suppl 1983;305:7-11. 2. Pai VB, Nahata MC. Drug dosing in pediatric patients. In: Murphy JE, ed. Clinical pharmacokinetics. 5 th ed. Bethesda, MD: Am Soc Healthsyst Pharm; 2011:29-44. 3. Vanpée M, Blennow M, Linné T, Herin P, Aperia A. Renal function in very low birth weight infants: normal maturity reached during early childhood. J Pediatr 1992;121:784-8. 4. Kearns GL. Pharmacogenetics and development: are infants and children at increased risk for adverse outcomes? Curr Opin Pediatr 1995;7:220-33. 5. Taketomo CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook, 22th ed. Hudson, OH: Lexi-Comp, 2015 6. Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Clin Pharmacokinet 1980;5:485-527. 7. Besunder JB, Reed MD, Blumer JL. Principles of drug disposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface. Clin Pharmacokinet 1988;14:189-216 8. Friedman CA, Parks BR, Rawson JE. Gentamicin disposition in asphyxiated newborns: relationship to mean arterial pressure and urine output. Pediatr Pharmacol (New York)1982;2:189-97. 9. Touw DJ, Graafland O, Cranendonk A, Vermeulen RJ, van Weissenbruch MM. Clinical pharmacokinetics of phenobarbital in neonates. Eur J Pharm Sci 2000;12(2):111-6. 10. Donn SM, Grasela TH, Goldstein, GW. Safety of a Higher Loading Dose of Phenobarbital in the Term Newborn. Pediatrics 1985;75(6):1061-4. 11. Heimann G, Galdtke E. Pharmacokinetics of Phenobarbital in Childhood. Eur J Clin Pharmacol 1977;12(4):305-10. 12. Yukawa M, Yukawa E, Suematsu F, et al. Population pharmacokinetics
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