Pediatric Infection and Vaccine

The Korean Society of Pediatric Infectious Diseases (대한소아감염학회)
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Voriconazole Therapeutic Drug Monitoring is Necessary for Children with Invasive Fungal Infection

소아에서 보리코나졸 치료적 약물 농도 모니터링의 임상적 의의

  • Kang, Hyun Mi (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Kang, Soo Young (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Cho, Eun Young (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Yu, Kyung-Sang (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine) ;
  • Lee, Ji Won (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Kang, Hyoung Jin (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Park, Kyung Duk (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Shin, Hee Young (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Ahn, Hyo Seop (Department of Pediatrics, Seoul National University Bundang Hospital) ;
  • Lee, Hyunju (Department of Pediatrics, Seoul National University Bundang Hospital) ;
  • Choi, Eun Hwa (Department of Pediatrics, Seoul National University Children's Hospital) ;
  • Lee, Hoan Jong (Department of Pediatrics, Seoul National University Children's Hospital)
  • 강현미 (서울대학교병원 소아청소년과) ;
  • 강수영 (서울대학교병원 소아청소년과) ;
  • 조은영 (서울대학교병원 소아청소년과) ;
  • 유경상 (서울대학교 의과대학 임상약리학교실) ;
  • 이지원 (서울대학교병원 소아청소년과) ;
  • 강형진 (서울대학교병원 소아청소년과) ;
  • 박경덕 (서울대학교병원 소아청소년과) ;
  • 신희영 (서울대학교병원 소아청소년과) ;
  • 안효섭 (분당서울대학교병원 소아청소년과) ;
  • 이현주 (분당서울대학교병원 소아청소년과) ;
  • 최은화 (서울대학교병원 소아청소년과) ;
  • 이환종 (서울대학교병원 소아청소년과)
  • Received : 2013.08.08
  • Accepted : 2013.10.15
  • Published : 2014.04.25
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Abstract

Purpose: To determine the clinical significance of voriconazole therapeutic drug monitoring (TDM) in the pediatric population. Methods: Twenty-eight patients with invasive fungal infections administered with voriconazole from July 2010 to June 2012 were investigated retrospectively. Fourteen received TDM, and 143 trough concentrations were analyzed. All 28 patients were assessed for adverse events and treatment response six weeks into treatment, and at the end. Results: Out of 143 samples, 53.1% were within therapeutic range (1.0-5.5 mg/L). Patients administered with the same loading (6 mg/kg/dose) and maintenance (4 mg/kg/dose) dosages prior to initial TDM showed highly variable drug levels. Adverse events occurred in 9 of 14 patients (64.3%) in both the TDM and non-TDM group. In the TDM group, voriconazole-related encephalopathy (n=2, 14.3%) and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (n=8, 57.1 %) occurred with serum levels in the toxic range (>5.5 mg/L), whereas blurred-vision (n=2, 14.3%) occurred within the therapeutic range (1.18 mg/L and 3.9 mg/L). The frequency of voriconazole discontinuation due to adverse events was lower in the TDM group (0.0% vs. 18.2%, P =0.481). Overall, 57.2% of the patients in the TDM group versus 14.3% in the non-TDM group showed clinical response after 6 weeks (P =0.055), whereas 21.4% in the TDM group versus 14.3% in the non-TDM group showed response at final outcome (P =0.664). In the TDM group, >67.0% of the serum levels were within therapeutic range for the first 6 weeks; however 45.5% were within therapeutic range for the entire duration. Conclusion: Routine TDM is recommended for optimizing the therapeutic effects of voriconazole.

목적: 본 연구는 소아 환자들에서 voriconazole 치료적 약물 농도 모니터링의 임상적 의의를 분석하고자 하였다. 방법: 2010년 7월부터 2012년 6월까지 서울대학교병원에 입원한 18세 이하의 소아 환자들 중, 침습성 진균감염증에 대해 voriconazole 치료를 받은 증례를 후향적 의무기록 분석을 통해 분석하였다. 본 연구에 포함된 총 28명의 환자 중 14명이 약물 농도 모니터링을 받았으며, 143개의 혈중 농도 측정 값을 분석하였다. 모든 환자들에게서 치료 효과 및 독성 증상 발현 여부를 파악하였다. 결과: 143개의 혈중 농도 측정 값 중 53.1%에서 치료적 범위(1.0-5.5 mg/L) 내에 들었고, 같은 용법으로 치료받았더라도 높은 혈중 농도 변동성(high variability)을 보였다. 약물 농도 모니터링을 받았던 군(TDM 군)과 받지 않았던 군(non-TDM 군)에서 각각 14명 중 9명(64.3%)이 독성 증상을 나타냈는데, TDM 군에서 신경학적 증상(n=2, 14.3%) 및 간기능 장애(n=8, 57.1%)는 높은 voriconazole 혈중 농도(>5.5 mg/L)를 보인 환자들에게서 나타났다. 반면, 시각 장애는 혈중 농도가 치료적 범위 내에 있을 때 발현하였다(1.18 mg/L, 3.9 mg/L). TDM 군에서 non-TDM 군에 비하여 독성 증상으로 인하여 약물을 중단했던 빈도가 낮았다(0.0% vs. 18.2%, P =0.481). 치료 시작 6주 후 치료 효과를 분석해본 결과 TDM 군의 57.2%에서 치료에 대한 반응을 보였으나, non-TDM 군에서는 14.3%에서 치료 반응을 보였다(P =0.055). 최종 치료효과 분석에서는 TDM 군의 21.4%에서 치료 반응을 보였으나, non-TDM 군의 14.3%에서 치료 반응을 보였다(P =0.664). TDM 군에서 치료 시작 첫 6주 동안 혈중 약물 농도를 분석했을 때 67.0% 이상에서 치료적 범위 내에 들었으나, 치료 기간 전체를 봤을 때에는 45.5%에서 치료적 범위 내에 들었다. 결론: 소아에서 voriconazole 사용 시 치료적 약물 농도 모니터링을 통하여 치료 목표를 효과적으로 달성하고, 독성이 나타나는 것을 예방할 수 있다.

Keywords

References

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