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.
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.
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 receive...
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.
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.
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문제 정의
The high morbidity and mortality of IFI warrants aggressive yet specified treatment, and because voriconazole has a narrow therapeutic margin and unpredictable serum levels, the awareness for therapeutic drug monitoring (TDM) is increasing. This study aimed to determine the implications of voriconazole TDM on the clinical outcome and adverse events in pediatric immunocompromised patients.
제안 방법
A quantitative analysis of voriconazole was performed using high-performance liquid chromatography (1200 series, Agilent Technologies, United States) coupled with tandem mass spectrometry (API3200, Applied Biosystems/MDS sciex, United States). Trough levels were measured by obtaining blood samples 30 minutes before the next scheduled dosing of voriconazole.
Many of the patients who received monitoring of serum voriconazole levels had a more severe and unstable course, and the treatment duration lasted for a longer period. Another limitation in this study was determining to what degree the underlying conditions of the patients affected their voriconazole levels and frequency of side effects.
In the TDM group, 3 patients did not receive loading doses, whereas in the non-TDM group, 1 patient did not receive loading doses. Patients in the TDM group received dosage adjustment after the initial TDM sampling if the levels were below or above the therapeutic level, and the next TDM sampling occurred 7 days after adjustments were made.
Patients in the TDM group were analyzed to observe how adverse events correlated with toxic drug levels. The two patients with voriconazole-related encephalopathy displayed their symptoms while serum levels were in the toxic range.
To observe differences in the outcome between the TDM and non-TDM group, patients were assessed at 6 weeks after initiating voriconazole, and at final outcome (Table 3). Of the 14 patients that did not receive TDM, two (14.
대상 데이터
A total of 143 serum trough concentrations were taken from 14 patients (median 7.5 samples per patients, with the range at 1 to 32). With the therapeutic range set at 1.
Between July 2010 and June 2012, a total of twenty-eight patients aged 18-years old or younger were included in this study. All patients who received voriconazole at least once for treatment or prophylaxis of IFI were included.
데이터처리
* Pearson Chi square test.
In order to compare categorical variables for baseline characteristics, Fisher’s exact test, Pearson Chi square test, and Mann-Whitney U test was used.
이론/모형
For adverse events and treatment outcome, the Fisher’s exact test was used.
성능/효과
Both patients that displayed voriconazole-related encephalopathy in our study had serum voriconazole levels in the toxic range for about three weeks, with one of the patient’s serum level peaking up to 6.57 mg/L, and the other 11.75 mg/L.
By final outcome, 2 patients (14.3%) in the non-TDM group and 3 (21.4%) in the TDM group showed treatment success, with no statistically significant difference in the end result between the two groups (P=0.664).
3%) in both the TDM and non-TDM group experienced adverse events (Table 2). In both groups, 8 out of 14 patients (57.1%) experienced AST or ALT elevation greater than 5-fold of their baseline levels measured prior to initiating voriconazole. Two patients (14.
In conclusion, routine monitoring of serum voriconazole levels in pediatric patients with suspicious IFI is strongly recommended for optimizing therapeutic response, especially as many factors contribute to the high variability in serum levels of children. Also, adverse events frequently occur during voriconazole administration, and monitoring serum levels allow physicians to continue treatment of IFI and avoid withdrawing the drug unnecessarily, enabling aggressive treatment for IFI.
, therefore we examined the difference in the outcome of patients within the TDM group depending on the percentage of voriconazole levels that remained within therapeutic range. In the TDM group, the patients were able to maintain an average of 67.0% of their serum voriconazole levels within therapeutic range during the first 6 weeks of treatment. But by the end of therapy, patients were only able to maintain an average of 45.
Six patients had proven IFI (4 patients with invasive aspergillosis, 1 patient with mucormycosis, and 1 patient with invasive candidiasis), 13 patients had probable IFI (all 13 patients with invasive aspergillosis), 4 patients had possible IFI, and 5 patients were prophylactically administered with voriconazole. Of the 28 patients, 14 (50.0%) received voriconazole TDM, and a total of 143 trough concentrations were measured.
Table 1 shows the characteristics of the patients included in this study. The baseline characteristics of the patients showed no significant statistical difference between the TDM and non-TDM groups, except the median duration of treatment (57.5 days in the TDM group versus 13.5 days in the non-TDM group, P=0.009).
The final outcome, on the other hand, showed no clinically significant difference in the outcome among the two groups, where most of the patients’ IFI aggravated (P=0.664).
The outcome of IFI was assessed at 6 weeks after beginning voriconazole therapy and at final outcome. Six weeks was chosen for outcome assessment because in invasive aspergillosis, clinical response to therapy may be evident by 2-6 weeks16) .
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