(The) effect of solute carrier organic transporter family member 2B1 genotype and cytochrome P450 3A activity on the pharmacokinetic characteristics of voriconazole

이상원 서울대학교 대학원 2020 국내박사

서론: Voriconazole의 높은 약동학적 변동성은 주로 CYP2C19의 유전형에 의해 설명할 수 있지만, 아직 변동성에 기여하는 인자 중 밝혀지지 않은 것들이 많다. 방법: 본 연구에서는 solute carrier organic anion transporter family member 2B1 (SLCO2B1)의 유전형이 voriconazole의 약동학에 미치는 영향을 탐색하고자 12명의 건강한 CYP2C19 poor metabolizer를 대상으로 voriconazole 200 mg을 단회 정맥 또는 경구 투여하였다. 모델 기반 시뮬레이션을 통해 voriconazole 반복 투여 시 SLCO2B1 유전형이 약동학에 미치는 영향을 탐색하였다. 추가로, CYP3A4 효소의 활성도가 voriconazole의 약동학에 미치는 영향도 탐색하였다. 결과: Voriconazole 경구 투여 시 SLCO2B1 c.*396T>C variant type 대상자들은 wild type 대상자들에 비해 voriconazole의 흡수가 감소하는 양상이 관찰되었다. 하지만, 본 연구에서 측정된 CYP3A 활성도 표지자들은 voriconazole의 대사와 유의한 상관관계를 보이지 못했다. 모델 기반 시뮬레이션 결과, SLCO2B1 유전형은 voriconazole 표준 용법 반복 투여 시 치료적 범위에 도달하는 확률에 유의한 영향을 미치지 않았다. 결론: 본 연구의 결과는 SLCO2B1 c.*396T>C이 장내 OATP2B1의 기능 저하와 연관되었을 가능성과 voriconazole의 개인간 약동학적 변이에 기여할 수 있음을 시사한다. 추가적인 연구를 통해 이러한 결과의 임상적 유의성을 확인할 필요가 있다. Introduction: High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. Methods: In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. A model-based simulation was done to further explore the effect of SLCO2B1 genotype on the pharmacokinetics of voriconazole. In addition, the influence of CYP3A4 enzyme activity was also explored. Results: The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild-type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. SLCO2B1 genotype did not seem to have a significant effect on the probability of reaching therapeutic range after a standard voriconazole dosing regimen. Conclusions: The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to inter-individual PK variability of voriconazole. The clinical relevance of these findings should be confirmed through further investigations.

Physiologically based pharmacokinetic modeling of voriconazole for personalized pharmacotherapy in different CYP2C19 genotypes

Oh, Kyungyul Sungkyunkwan university 2021 국내석사

Voriconazole, which is commercialized under the brand name Vfend, is a second-generation triazole antifungal agent and is used for the treatment of many fungal infections. Specifically, the American Infectious Diseases Association (IDSA) recommends voriconazole as a first-line treatment for invasive aspergillosis (IA). In many studies, it is known that the genetic polymorphism of CYP2C19 according to individuals shows pharmacokinetic differences for voriconazole. In vitro studies have shown that the liver metabolism of voriconazole is mainly mediated by liver cytochrome P450 2C19 (CYP2C19) and less mediated by CYP2C9 and CYP3A4. So, preferentially I figured out the CYP2C19 genetic polymorphism effects on drug metabolism using physiologically based pharmacokinetic (PBPK) modeling. For the development of voriconazole PBPK model in the PK-SIM® software, demographic, physicochemical, absorption, distribution, metabolism, and excretion parameters according to CYP2C19 genetic polymorphism were applied through reference or experiment. Thirty-nine healthy Korean clinical PK data were used according to the CYP2C19*1/*1 (n=13), CYP2C19*1/*2, CYP2C19*1/*3 (n=13), and CYP2C19*2/*2, CYP2C19*2/*3, CYP2C19*3/*3 (n=13) referring to the Korea Food and Drug Administration (KFDA) report. In order to apply the metabolic rate by CYP2C19 genetic polymorphism, in-vitro metabolism was performed using HPLC-MS/MS. Based on the created model, AUCend, AUCinf, Cmax, Tmax, T1/2, and CL were calculated in PK-SIM® software. As a result, the AUCend of CYP2C19*1/*1 was 15535 ng/h/mL, the AUCend of CYP2C19*1/*2, CYP2C19*1/*3 was 26544 ng/h/mL, and the AUCend of CYP2C19*2/*2, CYP2C19*2/*3, CYP2C19*3/*3 was 43415 ng/h/mL, indicating that there is a significant difference. A two-fold error was used for model evaluation and all PK parameters were satisfied. Validation was conducted to see if the developed voriconazole PBPK model was suitable for other races, and all but some satisfied two fold errors. Therefore, these results demonstrate that a model has been successfully created to predict the pharmacokinetic parameters of voriconazole in relation to the CYP2C19 genotypes. Finally, I hope that personalized pharmacotherapy will be applied based on the disposition of voriconazole considered in this study. 보리코나졸은 다양한 곰팡이 감염을 치료하는데 사용되는 항진균제이다. 특히 침습성 아스페리길루스증에 대하여 1차 치료제로 권고되는 약물이다. 이 약물의 대사는 CYP2C19 효소에 의해서 주로 대사되는 것으로 알려져 있으며, 시험관 내 연구에 따르면 보리코나졸의 대사는 주로 간 사이토크롬 P450 2C19 (CYP2C19)에 의해 매개되고 CYP2C9 및 CYP3A4에 의해 덜 매개된다고 알려져 있다. 기존의 연구에는 단순히 전체의 간 혈장 청소율, 또는 CYP2C19 유전형에 따라 간에 들어있는 CYP2C19 효소의 함량을 가지고 대사 정도를 관찰했다면, 이번 연구에서는 직접 시험관 내 실험을 통해 CYP2C19 효소의 대사 속도를 이용하여 대사 정도를 관찰하는 것이다. 시험관 내 효소 대사 실험을 통해서 보리코나졸에 대한 CYP2C19*1 야생형 재조합 단백질의 반응 대사 속도를 구할 수 있었지만, CYP2C19의 돌연변이 단백질인 CYP2C19*2, CYP2C19*3의 같은 경우 효소 활성이 없기 때문에 실험을 진행할 수 없었다. 따라서 CYP2C19*2, CYP2C19*3 그룹에서는 간 혈장 청소율로 최적화를 나타내었다. 보리 코나 졸 PBPK 모델 개발을 위해 보리코나졸의 물리 화학적 특성 및 유전형에 따른 약동학적 매개변수 들을 종합하여 만들었다. 만들어진 모델의 평가를 위해서 식품 의약품 안전처 (KFDA) 보고서를 참고하였고 CYP2C19 유전자형에 따라 39명의 건강한 한국 임상 PK 데이터를 기반으로 평가를 실시하였다. 실험 결과를 바탕으로 AUCend, AUCinf, Cmax, Tmax, T1/2 및 CL은 모델링에서 계산되었으며 KFDA 보고서의 보리코나졸 임상 PK 매개 변수와 비교했을 때 허용 기준 (two-fold error)을 만족하였다. 추가 문헌조사를 통해서 다른 인종에서의 건강한 성인을 대상으로 한 보리코나졸 임상 PK 데이터를 참고하여, 만들어진 모델의 벨리데이션 작업을 실시하였고 대체로 허용기준을 만족하는 결과를 얻을 수 있었다. 위 연구는 직접 시험관 내 실험을 이용하여 대사의 매개변수에 적용시켜 CYP2C19 유전적 다형성과 관련해서 보리코나졸의 생리학적 기반 약물 동태 모델을 처음으로 개발하였다. 이 모델을 통해서 특정 약물을 대사 시키는 효소의 유전적인 요인이 미치는 영향에 대해서 알려주며, 어느 약물에 대해서라도 임상 약동학적 매개변수가 존재한다면 위와 같은 방식으로 모델을 개발할 수 있는 지표가 된다. 결과적으로 본 연구에서 고려한 보리코나졸의 약동학 특성을 바탕으로 개인화 된 약물 요법이 적용될 수 있기를 바란다.

Effects of loganin on the pharmacokinetics of voriconazole in rats with acetaminophen-induced hepatotoxicity

박기현 아주대학교 일반대학원 2024 국내석사

Voriconazole, an antifungal agent belonging to the triazole class, is effective against mold infections. Fungal infections are common in patients with immune diseases. In this experiment, acetaminophen induces liver toxicity in mice, confirming changes in the pharmacokinetics of voriconazole. It also investigates changes in liver protection when affected by loganin and its effect on the pharmacokinetics of voriconazole. Pharmacokinetic studies involved the administration of voriconazole via both intravenous and oral routes to rats. Tests were performed to evaluate the drug's plasma levels through both intravenous (at 10 mg/kg) and oral (at 20 mg/kg) administration of voriconazole. To verify metabolism within liver microsomes, calculations were made for the maximum velocity (Vmax), Michaelis-Menten constant (Km), and intrinsic clearance (CLint) for metabolic processes occurring in both liver and intestinal microsomes. After intravenous or oral administration of voriconazole, the total area under the plasma concentration time curve (AUC) of the APAP rats, which is a hepatotoxic model, was significantly larger than that of the AL rats administered with loganin, which is a protective substance. In addition, there was also a decrease in the time mean gap (CL). In an in vitro metabolic study, the APAP rats showed reduced levels of CYP2C19 and CYP3A4 in the liver, and subsequently recovered from the AL rats. In vitro metabolic studies, in liver microsomes, the APAP rats reduced Vmax and CLint. In conclusion, in the APAP rats, there was an absence of voriconazole metabolism and excretion, leading to an AUC increase due to reduced CL. It was confirmed that the AUC recovered compared to the APAP rats when loganin (AL rats) was administered, alongside restored CYP expression and enzyme activity. The restoration of voriconazole metabolism and AUC was confirmed upon concurrent administration of loganin. Key words: voriconazole, acetaminophen, loganin, CYP3A1/2, CYP 2C19

Inductive effect of rifampin on the clinical pharmacokinetics of voriconazole and related biomarkers

이승환 서울대학교 대학원 2012 국내박사

Voriconazole is a triazole antifungal agent used to treat invasive aspergillosis, and is metabolized by the CYP2C19, CYP2C9, and CYP3A via N-oxidation. MicroRNAs are small non-coding RNA molecules that play an important role in the regulation of gene expression. This study evaluated the effect of a potent CYP inducer, rifampin, on the pharmacokinetics (PKs) of voriconazole according to CYP2C19 genotype and the possibility of circulating microRNAs as representative biomarkers in healthy subjects. An open-label, single-sequence study was conducted in twelve healthy subjects consisting of each of 6 CYP2C19 extensive metabolizers (EMs; *1/*1) and poor metabolizers (PMs; *2/*2, *2/*3, *3/*3). On the first day, subjects were orally administered a single dose of voriconazole 400 mg. From the next day, they received oral rifampin 600 mg once a day for 6 days followed by coadministration of rifampin with voriconazole. Serial blood samples were taken on the day of voriconazole administration. Plasma concentrations of voriconazole and voriconazole-N-oxide were measured by high performance liquid chromatography – tandem mass spectrometry and PK parameters were calculated using noncompartmental methods. Serum microRNA (miR-16, -18a, -27a, -27b, -122, -148a, -223 and -451) were quantified by real-time reverse transcription-polymerase chain reaction. When voriconazole was administered with rifampin, the apparent clearance of voriconazole was significantly increased from 23.5 ± 15.7 L/h to 252.3 ± 201.5 L/h and the major metabolite of voriconazole, voriconazole-N-oxide, was more rapidly produced and eliminated. The metabolic ratio (voriconazole-N-oxide / voriconazole) was changed from 3.7 ± 2.4 to 5.7 ± 4.2 by rifampin. The relative changes of apparent clearance and metabolic ratio did not differ significantly between CYP2C19 genotypes. The serum miR-27a and miR-27b levels were increased 1.32 times and 1.75 times after rifampin coadministration, respectively, but obvious changes were not observed in the other microRNAs between before and after rifampin coadministration. Induction of CYP enzyme by rifampin significantly reduced the systemic exposure of voriconazole regardless of CYP2C19 genotype and the changes in serum microRNA levels related to enzyme expression were observed. 보리코나졸 (voriconazole)은 트리아졸계 항진균제 (triazole antifungal agent)로 침습성 아스페르길루스증 (invasive aspergillosis) 치료에 이용되며, CYP2C19, CYP2C9 그리고 CYP3A4 효소에 의해 N-oxidation 과정으로 대사된다. 마이크로 RNA (microRNA)는 발현되지 않는 작은 RNA (small non-coding RNA)로, 유전자 발현 조절에 중요한 역할을 한다. 이 연구는 건강 자원자에서 CYP 유도제인 리팜핀 (rifampin)이 보리코나졸의 약동학에 미치는 영향을 CYP2C19 유전형에 따라 평가하고, 관련 생체표지자로서의 가능성을 평가하고자 하였다. 공개, 단일군 연구가 CYP2C19 extensive metabolizers (EM 군; *1/*1 유전형) 6 명과 CYP2C19 poor metabolizers (PM 군; *2/*2, *2/*3, *3/*3 유전형) 6 명으로 구성된 12명의 건강 자원자에서 수행되었다. 연구 첫날 자원자들은 보리코나졸 400 mg 을 경구로 투여 받았다. 다음날부터 자원자들은 리팜핀 600 mg 을 6일 동안 1일 1회 투여 받았으며, 그 다음날 리팜핀과 보리코나졸을 동시에 투여 받았다. 보리코나졸 투여일에 약동학 분석과 마이크로 RNA 측정을 위한 채혈이 이루어졌다. 혈중 보리코나졸 및 보리코나졸-N-옥사이드 (voriconazole-N-oxide) 농도는 high performance liquid chromatography – tandem mass spectrometry 로 측정하였으며, 약동학적 파라미터들은 비구획 방법 (noncompartmental methods)으로 산출하였다. 혈중 마이크로 RNA 16 (miR-16), 18a (miR-18a), 27a (miR-27a), 27b (miR-27b), 122 (miR-122), 148a (miR-148a), 223 (miR-223) 및 451 (miR-451) 의 양을 real-time reverse transcription-polymerase chain reaction 방법으로 측정하였다. 보리코나졸과 리팜핀을 병용 투여 하였을 때, 보리코나졸의 겉보기 청소율 (apparent clearance)은 23.5 ± 15.7 L/h 에서 252.3 ± 201.5 L/h 로 유의하게 증가하였으며, 주 대사체인 보리코나졸-N-옥사이드는 더 빠르게 생성되었다 제거되었다. 보리코나졸에서 보리코나졸-N-옥사이드로의 대사율 (metabolic ratio) 은 3.7 ± 2.4 에서 5.7 ± 4.2 로 변화하였다. 겉보기 청소율과 대사율의 상대적인 변화는 CYP2C19 유전형에 따른 유의한 차이가 관찰되지 않았다. 혈중 마이크로 RNA 27a (miR-27a)와 27b (miR-27b)는 리팜핀 투여 후에 각각 1.32 배, 1.75 배 증가하였다. 하지만 다른 마이크로 RNA 들에서는 명확한 변화가 관찰되지 않았다. 리팜핀에 의한 CYP 효소 유도 효과는 보리코나졸의 체내 노출을 CYP2C19 유전형과 관계없이 유의하게 감소시켰으며, 대사 효소 발현과 관련된 혈중 마이크로 RNA의 변화가 관찰되었다.

폐이식 환자의 itraconazole과 voriconazole 투여 시 tacrolimus와의 상호작용 연구

정유진 연세대학교 대학원 2016 국내석사

본 연구는IAP 를 예방 또는 치료를 위해 항진균제를 투여 받는 폐이식 환자에서 itraconazole 또는 voriconazole처방 시 tacrolimus의 약물농도 변화를 비교하고, 이들과의 상호작용 정도를 확인하여 폐이식 환자의 tacrolimus의 농도변화 예측에 실마리를 제공함으로써 폐이식 환자에서 안전하고 효과적인 진균감염의 예방과 치료 약물요법 제안에 기여하고자 수행되었다. 2012년 9월 1일 ~ 2015년 5월 31일, 33개월 동안 연세대학교 세브란스병원에 입원한 전체 환자 중 Electronic medical record (EMR)에 폐이식 진단명(Z94.2)이 입력된 환자를 대상으로 후향적 관찰 연구를 진행하였다. Tacrolimus를 복용하는 폐이식 환자에게 입원 기간 동안 7일 이상 itraconazole 또는 voriconazole이 처방된 두 군으로 나누어, 항진균제 투여 기간 동안 환자의 체중과 하루 tacrolimus의 용량 대비 tacrolimus의 평균 혈중 농도를 1차 결과로 정하고, 총 tacrolimus의 혈중농도 검사 횟수 대비 목표 농도(5 ~ 15 ng/mL)를 벗어나는 tacrolimus의 혈중농도 결과 횟수 비율을 2차 결과로 분석하였다. Itraconazole 사용 환자군과 voriconazole 사용 환자군에서 tacrolimus의 일 평균 용량은 1.77 ± 1.03 mg/d vs. 2.39 ± 2.76 mg (p= 0.293), 환자의 체중 대비 tacrolimus 일 평균 용량 차이는 0.03 ± 0.02 mg/kg/d vs. 0.05 ± 0.06 mg/kg/d였다(p=0.281). Tacrolimus의 평균 혈중 농도는 10.49 ± 2.35 ng/mL vs. 10.95 ± 2.98 ng/mL 이었으며(p=0.456), 환자의 체중과 일 평균 용량 대비 tacrolimus 평균 혈중 농도는 472.14 ± 342.21 (ng/mL)/(mg/kg/d) vs. 767.60 ± 1209.65 (ng/mL)/(mg/kg/d) 였다(p=0.250). 총 tacrolimus 혈중농도 검사 횟수 대비 목표농도인 5 ~ 15 ng/mL 내인 백분율로 환산한 비율은 17.97 ± 13.33% vs. 24.40 ± 18.48% 였다(p=0.129). Tacrolimus를 투여 받는 폐이식 환자에게 itraconazole과 voriconazole 의 투여 기간 동안 환자의 체중과 하루 tacrolimus의 용량 대비 tacrolimus의 혈중 농도와 총 tacrolimus의 혈중농도 검사 횟수 대비 목표 농도(5 ~ 15 ng/mL)를 벗어나는 tacrolimus의 혈중농도 결과 횟수 비율은 통계적인 차이가 없었다. 하지만 voriconazole을 투여 받던 몇몇 환자들에게 특이점들이 발견되어 추후 대규모, 다기관의 전향적인 연구가 필요하며 tacrolimus 농도뿐만 아니라 voriconazole의 농도를 관찰함으로써 안전하고 효과적인 진균감염의 예방과 치료 약물요법이 이루어져야 한다. This study was performed to compare the changes in the blood concentrations of tacrolimus when either itraconazole or voriconazole is together with tacrolimus to prevent or treat IAP in patients with lung transplants. Therefore we can compare the degree of drug-drug interactions between tacrolimus and itraconazole against tacrolimus and voriconazole. Patients who were admitted at Yonsei University Severance Hospital and had lung transplants coded as ‘Z94.2’ on Electronic Medical Record from September 2012 to May 2015 were analyzed retrospectively. The patients were divided into two groups-one is tacrolimus with itraconazole and the other is tacrolimus with voriconazole. Patients who took itraconazole or voriconazole for at least 7 days during tacrolimus administration were included. The primary outcome was comparing the mean tacrolimus concentration over the dose of tacrolimus per kg of body weight per day ((ng/mL)/(mg/kg/d)) when co-administered with either itraconazole or voriconazole. The secondary outcome was comparing the ratio of the number of results when tacrolimus blood concentrations are out of the target ranges (5~15 ng/mL) to the total number of tacrolimus blood concentration results. Mean tacrolimus dose per day between itraconazole group vs. voriconazole group was 77 ± 1.03 mg/d vs. 2.39 ± 2.76 mg (p= 0.293), mean tacrolimus dose per weight per day was 0.03 ± 0.02 mg/kg/d vs. 0.05 ± 0.06 mg/kg/d (p=0.281). Mean tacrolimus concentration was 10.49 ± 2.35 ng/mL vs. 10.95 ± 2.98 ng/mL (p=0.456), mean concentration of tacrolimus over the dose of tacrolimus per weight per day was 472.14 ± 342.21 (ng/mL)/(mg/kg/d) vs. 767.60 ± 1209.65 (ng/mL)/(mg/kg/d)(p=0.250). The ratio ofthe number of the results out of target tacrolimus concentrations to the total number of tacrolimus concentration results was 17.97 ± 13.33% vs. 24.40 ± 18.48% (p=0.129). There were no significant differences between itraconzaole and voriconazole to have influences on mean concentrations of tacrolimus over tacrolimus dose per weight per day. However there were a few singularities in some patients taking voriconazole. Therefore, further study is necessary in order to perform a multicenter, large scale and prospective study. Safer and more effective drug management to prevent and treat fungal infections should be done by therapeutic drug monitoring not only of tacrolimus but of itraconazole and voriconazole in lung transplant patients.

보리코나졸의 Therapeutic Drug Monitoring을 위한 최적의 채혈시각 탐색을 위한 시뮬레이션 연구

최승찬 울산대학교 대학원 2022 국내석사

Objective: Voriconazole is a broad-spectrum triazole antifungal agent with activity against a wide range of yeasts and filamentous fungi which has been approved worldwide for invasive fungal infections. It has a narrow therapeutic range, nonlinear pharmacokinetic profile, and high interindividual variability. Area under the time-concentration curve during 12-hour dosing interval (AUC0-12) and pre-dose concentration (Ctrough) are clinically important variables based on which dose adjustment is made. The purpose of this study is to explore optimal sampling time for therapeutic drug monitoring of voriconazole. Methods: Plasma voriconazole concentrations following three dosing regimens (Scenario 1, loading dose of 6 mg/kg IV q12hr on day 1, followed by maintenance dose of 4 mg/kg IV q12hr; Scenario 2, loading dose of 6 mg/kg IV q12hr on day 1, followed by 3 mg/kg IV q12hr; Scenario 3, loading dose of 6 mg/kg IV q12h on day 1, followed by 200 mg PO q12hr) were simulated to generate 1,000 sets of data for each scenario using NONMEM® (version 7.4.4). Using one or two concentration data early after the initiation of therapy, plasma concentration over time, AUC0-12, and Ctrough at steady state of each individual were predicted by maximum a posteriori (MAP) method. By comparing the accuracy and precision of these values, the optimal pharmacokinetic (PK) sampling time was explored. During the MAP prediction, deviation in sampling time from the planned time was also taken into account. Results: Plasma voriconazole concentration over time was well predicted by MAP method for all of the sampling times explored in this study with minimal bias (less than 10%). However, precision of predicted concentration was different by time points used in MAP, with low precision especially for the concentration around mid-point of the dosing interval. AUC0-12 was best predicted with high accuracy and precision using concentration at 2- or 3- hour sampling time in scenario 1 and 2. In scenario 3, AUC0-12 was well predicted with similar accuracies across all the sampling times of 1 through 12 hours, but the precision was predicted to be high when using later time points near 12 hour. Conclusions: We successfully reconstructed a voriconazole PK model and conducted a simulation study. The simulation suggested optimal sampling time points that can be implemented in clinical setting for the therapeutic drug monitoring of voriconazole. The current study provides useful information for individualized, optimal therapy of voriconazole.

Pharmacokinetic drug interaction between voriconazole and tofacitinib in rat

김효성 아주대학교 2021 국내석사

Tofacitinib has been demonstrated to treat rheumatoid arthritis (RA) as a Janus kinase (JAK) inhibitor (Fleischmann et al, 2012), among which it is a small molecule inhibitor specifically targeted for inhibition of JAK 1 and JAK 3 (Meyer et al, 2010). Citinib is also effective as a treatment for ulcerative colitis (Agnès et al, 2018). JAK is a downstream signaling molecule in many cytokine pathways involved in inflammatory bowel disease (IBD). When cytokines bind to cell surface receptors, ligand receptors dimerize, causing phosphorylation of JAK molecules. JAK then activates the signal transducer and activate of transcription molecules (STAT), which phosphorylation moves pass STAT to the nucleus and activate gene transcription (Soendergaard et al, 2018). By targeting the JAK signal, it can affect several cytokine pathways thought to be associated with colitis. The pharmacokinetics of tofacitinib are metabolized in the liver at about 70% clearance and excreted by the kidneys at about 30% clearance of the total clearance. In the liver clearance mechanism, CYP3A4 is mainly about 50% and CYP2C19 about 20% less (Dowty et al, 2014). Voriconazole is a triazole-based antifungal agent used in the treatment of candidiasis and aspergillus. According to the recent US guidelines, voriconazole has been recommended as a first-line therapy for aspergillosis (Misch and Safdar 2016).The mechanism of action of voriconazole is the inhibition of the cytochrome P450 (CYP450) dependent 14α lanosterol demethylation, an consequential echelon in the synthesis of cell membrane ergosterol, similar to other triazoles (Sanati et al, 1997). The metabolism of voriconazole show up in the liver through a family of CYP450 enzymes, including CYP2C9, CYP3A4, and CYP2C19 homologous enzymes. Metabolites have no antifungal activity. The activity of the CYP2C19 pathway, the main metabolic pathway of voriconazole, is highly dependant on genetic properties (Louis et al, 2003). The potential for drug interaction with voriconazole is high due to metabolism by the CYP 450 isoenzyme (Hoffman et al, 2002) The pharmacokinetics of voriconazole is most metabolized in the liver and is driven by CYP3A4. The half-life is approximately 6 hours and protein binding is about 58% (Changcheng et al, 2019). Tofacitinib is administered with antifungal agents such as voriconazole due to the risk of fungal infections such as upper respiratory tract infections (Yong et al, 2017). The purpose of this study is tofacitinib and voriconazole alone and in combination. It is to measure the blood concentration and pharmacokinetic parameters of drugs that change through co-administration. As a result, it is expected to be data for pharmacokinetic studies of tofacitinib and triazole-based drugs.

Preparation and evaluation of ophthalmic liposomal voriconazole formulation by thin film hydration method

황금길 Graduate School, Yonsei University 2018 국내석사

1. Introduction Fungal keratitis is one of infectious corneal diseases and is an increasing disease in developing countries. And the incidence is increasing in developed countries due to increased use of contact lenses. To treat this, antifungal agents are used, typically natamycin and amphotericin B. However, its use is limited because of the narrow range of antifungal agents and low permeability. Voriconazole, a second-generation azole antifungal agent with a broad range of antifungal agents, is under investigation. The limitation of Voriconazole is that it has low water solubility and poor cornea permeability. Liposome as nano-carrier can be used to overcome this problem. Voriconazole can be encapsulated between phospholipids of liposome to enhance permeability while increasing solubility. There are various ways of making liposomes. Among the various methods of making liposomes, liposomes were prepared by the commonly used thin film hydration method. Therefore, the goal of this paper is to develop a liposomal formulation of voriconazole with broad spectrum antifungal activity, which is increased water solubility and permeability, thereby increasing the BA of voriconazole and ultimately increasing therapeutic efficiency. 2. Preparation of liposome We prepared liposome by thin film hydration. Formulations of Increasing the organic solvent amount and molar ratio of HSPC were prepared. And we also prepared formulations containing a mPEG-DSPE, SA for positively charged liposome, and DP for negatively charged liposome. Cholesterol was added to find out effect of cholesterol to liposome. 3. Evaluation of liposome Organic solvent amount did not affect to size, zeta potential, assay%, EE%. Increasing molar ratio of HSPC affect to the size, PDI, and pH. Cholesterol did not affect to liposome size, PDI and assay%, EE%, also. Formulation with SPC was viscous and size was largest. mPEG-DSPE makes zeta potetial of liposome to negative charge but stearylamine makes zeta potential to positive. Dicetylphosphate makes liposome acidic but stearylamine makes liposome basic. Voriconazole assay % was almost 100% and EE% was almost 94% in all formulation. Specially formulation with mPEG-DSPE showed 99% of EE%. In the DSC data, voriconazole peak and cholesterol peak was disappeared in all formulations. In vitro release data described that all liposome formulation has higher dissolution rate than 1% voriconazole suspension. Formulation with mPEG-DSPE, Chol shows the higher dissolution rate. And permeation study with bovine cornea described that permeation rate followed the zeta potential. Formulation 12, and 15 have higher permeation rate and stearylamine formulation with positive zeta potential show lowest permeation rate. 진균 각막염은 감염성 각막 질환 중 하나이며 개발 도상국에서 증가하는 질병이다. 그리고 콘택트 렌즈의 사용 증가로 인해 선진국에서는 그 빈도가 증가하고 있다. 이를 치료하기 위해 일반적으로 natamycin과 amphotericin B와 같은 항진균제가 사용된다. 그러나 이들 항균제들은 항균 범위가 좁고 각막 침투성이 낮기 때문에 사용이 제한됩니다. 보리코나졸 (Voriconazole)은 다양한 종류의 항진균 범위를 가진 2 세대 azole계 항진균제이다. 보리코나졸의 사용 제한점은 용해도가 낮고 수분 안정성이 낮다는 것이다. 이 문제를 극복하기 위해 나노 운반체 인 리포좀을 사용할 수 있다. 보리코나졸은 리포솜의 인지질 사이에 encapsulation 되어 안정성이 높아지고 용해도도 높아질 수 있다. 리포솜을 제조하는 다양한 방법 중에서, 일반적으로 사용되는 thin film hydration법으로 리포좀을 제조 하였다. 따라서 본 연구의 목적은 용해도 및 투과성이 증가 된 광범위한 항진균 활성을 갖는 보리 코나 졸의 리포좀 제형을 개발함으로써 보리 코나 졸의 BA를 증가시키고 궁극적으로 치료 효율을 증가시키는 것이다. 2. 리포솜의 제조 Thin film hydration법을 리포솜을 만들었다. HSPC의 유기 용매량 및 몰비를 증가시키는 표뮬레이션을 개발 하였다. 그리고 우리는 또한 mPEG-DSPE, 양전하를 띤 리포솜을 위한 SA 및 음전하를 띠는 리포솜을 위한 DP를 함유하는 제제를 만들었다. 콜레스테롤이 리포솜에 대한 콜레스테롤의 효과를 알아 내기 위해 첨가되었습니다. 3. 리포좀의 평가 유기 용매의 양은 particle mean size, zeta potential, assay%, EE %에는 영향을 미치지 않았다. HSPC의 증가하는 몰 비율은 particle mean size, PDI, pH에 영향을 미친다. 콜레스테롤은 리포좀 mean size, PDI 및 assay%, EE%에도 영향을 미치지 않았다. SPC를 사용한 제제는 점성이 크고 입자 크기가 가장 컸다. mPEG-DSPE는 리간드의 제타 전위를 음전하로하지만 stearylamine은 리포솜의 zeta potential을 양전하로 만든다. dicetylphosphate는 리포좀을 산성으로 만들지만 stearylamine은 리포좀을 염기성으로 만든다. Voriconazole assay%은 거의 100 % 였고 EE %는 거의 모든 포뮬레이션에서 거의 94 %였다. 특히 mPEG-DSPE를 사용한 제제는 99 %의 EE %를 나타냈다. DSC 데이터에서 모든 포뮬레이션에서 보리코나졸 peak와 콜레스테롤 peak가 사라졌다. Drug release study는 모든 리포좀 제형이 1 % 보리코나졸 현탁액보다 높은 용출률을 갖는 것을 의미했다. Chol과 mPEG-DSPE을 함유한 포뮬레이션은 더 높은 용출률을 나타냈다. 소의 각막을 이용한 permeability study에서 permeability rate가 zeta potential과 비례한다고 할 수 있다. 포뮬레이션 12, 포뮬레이션 15는 보다 높은 permeability rate를 가지며, 양의 zeta potential을 갖는 stearylamine 포뮬레이션은 가장 낮은 투과 속도를 나타냈다.

Cytotoxicity of voriconazole on corneal endothelial cells

한상범 서울대학교 대학원 2011 국내박사

Microemulsion-based hydrogel formulation of voriconazole for topical delivery

김요한 서울대학교 대학원 2010 국내석사