Development of a sufficient design for estimation of fluconazole pharmacokinetics in people with HIV infection

AIMS

To assess an optimal design that is sufficient to gain precise estimates of the pharmacokinetic (PK) parameters for fluconazole in people with HIV infection.

METHODS

Two studies were identified, the first in healthy volunteers and the second in HIV patients. The investigators (J.F.R. and S.B.D.) were blinded to the second study results. The healthy volunteer study was modelled and a design was found to estimate the PK parameters. The design was evaluated by comparison of the standard errors of the parameters and the predictive performance of the optimal design. The predictive performance was assessed by comparing model predictions against observed concentrations for two models. The first model, termed ‘sufficient design’, was developed from data extracted from the HIV study that corresponded to the optimal design. The second model, termed ‘HIV outcome model’, by modelling all the data from the HIV study.

RESULTS

An optimal design HIV study was developed which had considerably fewer blood samples and dosing arms compared with the actual HIV study. The optimized design performed as well as the actual HIV study in terms of parameter precision. The performance of the design, described as the precision (mg l⁻¹)² (95% confidence interval) of the predicted concentrations to the actual concentrations for the ‘sufficient design’ and ‘HIV outcome model’ models were: 0.63 (0.40, 0.87) and 0.56 (0.32, 0.79), respectively.

CONCLUSION

This study demonstrates how data from healthy volunteers can be utilized via optimal design methodology to design a successful study in the target population.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Optimal design is being employed more frequently to help reduce the number of samples taken per patient, the number of patients and number of doses to be given within a study.
• In doing this the economic and patient resources required to conduct a population pharmacokinetic or pharmacokinetic–pharmacodynamic study are reduced.

WHAT THIS STUDY ADDS

• This is the first time that healthy volunteer data (e.g. from Phase I) have been used to develop an optimal design that is to be conducted in a population with different characteristics due to disease (e.g. Phase II).

     

氟康唑胶囊在健康人体的药代动力学及生物等效性

目的建立人血浆氟康唑(抗真菌药)HPLC测定法,比较氟康唑2种制剂在健康志愿者体内的药代动力学和相对生物利用度。方法用随机开放交叉试验设计,20名健康志愿者分别单剂量口服试验和参比制剂氟康唑胶囊300mg,用高效液相色谱法法测定血药浓度,计算2制剂的药代动力学参数,并进行生物等效性评价。结果试验和参比制剂氟康唑胶囊的主要药代动力学参数t1/2分别为(31.20±3.98),(31.51±3.26)h;tmax分别为(2.83±0.37),(2.65±0.24)h;Cmax分别为(6.20±1.08),(6.11±1.01)μg·mL-1;AUC0-96分别为(208.42±21.77),(200.27±18.27)μg·h·mL-1;AUC0-∞分别为(234.00±24.56),(227.14±20.91)μg·h·mL-1。各药代动力学参数无显著性差异(P>0.05)。试验制剂氟康唑胶囊相对生物利用度F为(104.3±8.5)%。结论2制剂具有生物等效性。     

早产儿氟康唑群体药动学模型的外部验证和剂量优化

目的:验证现有的早产儿氟康唑群体药动学模型对外部数据的预测准确性,并对给药剂量进行优化,为早产儿的个体化给药提供参考.方法:通过文献检索,提取国内外已发表的关于氟康唑的早产儿群体药动学模型信息.收集30例使用氟康唑的早产儿临床资料和血药浓度数据,采用拟合优度法、可视化预测检验法(visual predictive ch...     

固相萃取-高效液相色谱法测定人血浆中氟康唑浓度及其药动学研究

目的:建立测定人体血浆中氟康唑浓度的高效液相色谱法,并对供试制剂与参比制剂的生物等效性进行评价.方法:血样处理采用固相萃取方法,萃取小柱用甲醇活化后加入血浆1 mL,过柱后用含20%甲醇的水溶液1.0 mL洗涤,再用0.2 mL甲醇洗脱收集,取20 μL进样.色谱柱为C18柱 (150 mm×4.6 mm,5 μm),流动相为0.01 mol·L-1磷酸二氢钾(用磷酸调pH值为5.0)-乙腈(75:25);流速为1.0 mL·min-1,检测波长为267 nm.人体药动学试验采用双周期交叉设计方案,将18例志愿受试者随机分为2组,分别口服氟康唑供试胶囊和参比胶囊150 mg.结果:本方法线性范围为0.1～6.4 mg·L-1,r=0.999 9,最低检测浓度为0.1 mg·L-1,方法回收率为95.7%～108.0%,日内、日间RSD均小于15%,供试制剂与参比制剂主要药动学参数经统计学分析差异无显著性,供试制剂的相对生物利用度为(105.7±12.6)%.结论:本方法灵敏度高,特异性强,重现性好,供试制剂与参比制剂具有生物等效性.     

氟康唑片在中国维吾尔族和汉族健康人体内的药代动力学

目的 研究氟康唑片(抗真菌药)在中国维吾尔族和汉族健康人体内的药代动力学.方法 10名维吾尔族和10名汉族健康受试者,口服氟康唑片200 mg,用高效液相色谱法测定血浆中氟康唑浓度,用DAS Ver 2.0软件计算药代动力学参数.结果 氟康唑片在维吾尔族和汉族健康受试者的主要药代动力学参数:Cmax分别为(4.99±1.05)、(4.91±0.67)mg·L-1,tmax分别为(2.30±0.95)、(1.90±0.91)h,t1/2分别为(30.47±6.27)、(31.41±2.90)h,AUC0-96分别为(176.26±22.08)、(190.08±33.17)mg·h·L-1,AUC0-∞分别为(199.93±30.18)、(218.18±40.43)mg·h·L-1.结论 维吾尔族和汉族受试者单剂量口服氟康唑片药代动力学参数的差异无统计学意义.     

Pharmacokinetics of fosfluconazole and fluconazole following multiple intravenous administration of fosfluconazole in healthy male volunteers

AIMS: To assess the bioavailability of fluconazole (FLCZ) from phosphate pro-drug (fosfluconazole), to investigate the effect of loading doses on the time to achieve FLCZ steady state plasma concentrations and on safety, and to investigate the pharmacokinetics of fosfluconazole following once daily multiple bolus injection of fosfluconazole in healthy male volunteers. METHODS: The first study was a randomized, double-blind, double dummy, two-period crossover study. Subject received either 1000 mg fosfluconazole or 800 mg FLCZ once daily for 14 days in random order. The second study was an open label, randomized parallel group study. Subjects received one of three fosfluconazole once daily treatments: 500 mg for 10 days (no loading dose), a loading dose of 1000 mg on day 1 followed by 500 mg for 9 days (one loading dose), or loading doses of 1000 mg on days 1 and 2 followed by 500 mg for 8 days (two loading doses). RESULTS: The estimated mean (90% CI) bioavailability of FLCZ from fosfluconazole was 96.8% (94.5, 99.2), with a C(max,ss) ratio of 98.3% (93.3, 103.5) in the first study. Less than 1% of the administered dose of fosfluconazole was excreted unchanged in the urine and the majority (85.6%) was eliminated in the urine as FLCZ. In the second study two loading doses regimen led to earlier achievement of target steady state plasma concentrations (by day 3) compared with use of one or no loading dose (towards the end of the dosing period). Similar adverse event profiles were seen in all three treatment groups. Fosfluconazole did not accumulate after multiple dosing. CONCLUSIONS: Multiple administration of 1000 mg fosfluconazole and 800 mg FLCZ produced equivalent systemic exposure to FLCZ. Steady state FLCZ plasma concentrations were achieved earliest when two loading doses were used.     

中国汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学考察

目的研究汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学。方法健康汉族和朝鲜族受试者各10名,男女各半,口服氟康唑片200 mg,定时采血,用RP-HPLC法测定血药质量浓度,用drug and statistics(DAS 2.0.1)软件程序进行数据处理,用SPSS软件程序进行统计分析。结果汉族和朝鲜族受试者主要药物动力学参数ρmax为(4.91±0.67)、(4.70±0.86)mg.L-1;tmax为(1.90±0.90)、(2.55±1.07)h;t1/2为(33.07±5.90)、(31.02±6.02)h;AUC(0-96)为(189.61±32.91)、(183.75±31.83)mg.h.L-1,AUC(0-∞)为(219.21±40.46)、(209.93±46.37)mg.h.L-1。统计结果显示两民族受试者主要药物动力学参数差异无统计学意义。结论汉族、朝鲜族两民族的种族差异对氟康唑片的药物动力学无影响。     

单剂量口服氟康唑片在中国汉族和蒙古族健康志愿者体内的药动学

目的研究汉族和蒙古族健康志愿者单剂量口服氟康唑片的药动学。方法健康汉族和蒙古族受试者各10名,男女各半,口服氟康唑片200 mg,定时采血,用反相高效液相色谱法测定血药浓度,DAS软件程序进行数据处理,SPSS软件程序进行统计分析。结果汉族和蒙古族主要药动学参数中ρmax分别为(4.91±0.67)、(4.52±0.86)mg.L-1;tmax分别为(1.90±0.90)、(1.55±0.44)h;t12分别为(33.07±5.90)、(28.20±6.18)h;AUC(0→96)分别为(189.61±32.91)、(173.95±40.41)mg.h.L-1;AUC(0→∞)分别为(219.21±40.46)、(192.61±45.30)mg.h.L-1。统计结果显示两民族间主要药动学参数差异无统计学意义。结论汉蒙种族差异对氟康唑的药动学无影响。     

早孕妇女口服氟康唑的群体药物动力学研究

目的应用WinNonmix药动学软件计算早孕妇女口服氟康唑150 mg后的群体药物动力学参数,并分析绒毛组织和血液组织中氟康唑的药物浓度相关性。方法以早期妊娠合并阴道假丝酵母菌感染欲行人流术的患者为研究对象,以氟康唑150 mg单剂量口服给药后在不同的时间点行人流术,同时留取实验对象的血液和绒毛组织,测定生物组织中的药物浓度,并进行数据处理。结果研究表明绒毛组织中药物浓度与血液中药物浓度呈正直线相关,直线回归方程为C胚胎=0.364 0×C血液＋0.020 08,相关系数为0.914,P〈0.005。氟康唑在早孕妇女胚胎和血液组织中大约6 d全部代谢完毕,无蓄积。经WinNonmix药动学软件处理,依据非线性混合效应模型计算表明：氟康唑符合一级吸收动力学,有滞后时间的一室模型。固定效应中,体重影响表观分布容积。结论氟康唑在早孕妇女胚胎组织和血液组织中的药物浓度存在显著差异,且符合直线正相关。 更多还原     

氟康唑类似物的研究进展

氟康唑是第三代三唑类抗真菌药物,具有水溶性好、广谱和低毒等优点,是临床上治疗真菌感染的首选药物。随着氟康唑耐药菌株的不断出现,研制新型氟康唑类似物成为重要的科研课题。通过对氟康唑结构的修饰,获得新型氟康唑类似物,为进一步的新药合成研究提供线索。     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

氟康唑在9个中国人体内的药物动力学

目的：了解中国健康人静脉滴注和口服氟康唑的药物动力学。方法：９例健康志愿者随机分为２组，静脉和口服交叉给予单剂量氟康唑３００ｍｇ，测定血、尿和唾液中药物浓度。结果：按非室模型计算针、片剂的药物动力学参数分别为：ＡＵＣ＝２６５±９３和２５８±７９μｇ·ｈ／ｍＬ；ＭＲＴ＝４３±２５和６９±６６ｈ；Ｔ１２β＝３２±２０和３２±２９ｈ；Ｃｌ＝１．３±０．４和１．２±０．４Ｌ／ｈ；Ｖｓｓ＝６１±５８和３６±１２Ｌ及ＡＶＥ＝３．７±１．３和３．５±１．１ｍｇ／Ｌ。结论：氟康唑的生物利用度为９７％，具有吸收好、分布广和Ｔ１２长的动力学特点     

米卡芬净与氟康唑预防造血干细胞移植真菌感染的临床对比观察

摘要： 目的 对比米卡芬净与氟康唑预防异基因造血干细胞移植 （Allo-HSCT） 患者早期侵袭性真菌病 （IFD） 的疗效。方法 回顾性分析外周血Allo-HSCT的82例患者, 观察组 （42例） 在预处理后粒细胞缺乏期间开始给予米卡芬净静脉滴注至白细胞稳定植入停用, 余时间给予氟康唑口服; 对照组 （40例） 全程给予氟康唑口服。随访至移植后 100 d, 对比2组IFD发生率、 药物不良反应发生率。结果 观察组和对照组IFD发生率分别为7.1% （3例） 和22.5% （9 例）, 差异有统计学意义 （χ2 =3.868, P＜0.05）; 2组真菌预防药物不良反应发生率分别为11.9% （5例） 和15.0% （6例）,差异无统计学意义 （χ2 =0.169, P＞0.05）; 2组应用ATG患者与未应用ATG患者IFD的发生率差异无统计学意义 （P＞ 0.05）。结论 Allo-HSCT真菌感染预防方案中, 米卡芬净联合氟康唑可有效降低移植患者早期IFD的发生率, 且未增加药物不良反应。     

氟康唑2种制剂在健康志愿者体内生物利用度和药物动力学比较

目的：比较氟康唑２种制剂在中国健康志愿者体内的药物动力学和生物利用度。方法：１０例中国健康志愿者随机交叉口服氟康唑２种（三维，辉瑞）胶囊各３００ｍｇ，采用反相ＨＰＬＣ法测定血中药物浓度。结果：氟康唑（三维）和氟康唑（辉瑞）ＡＵＣ分别为（２７９±６４）ｍｇ·ｈ／Ｌ和（２８９±５７）ｍｇ·ｈ／Ｌ；Ｃｍａｘ分别为（６．７±１．０）ｍｇ／Ｌ和（７．０±０．８）ｍｇ／Ｌ；Ｔｍａｘ分别为（１．９±０．７）ｈ和（１．９±０．７）ｈ；Ｔ１２β分别为（３７±７）ｈ和（３７±７）ｈ；Ｃｌ分别为（１．１４±０．２７）Ｌ／ｈ和（１．０８±０．２２）Ｌ／ｈ；Ｖｄ分别为（４１±２２）Ｌ和（３５±１１）Ｌ；Ｋｅ分别为（０．０４０±０．０１０）／ｈ和（０．０３０±０．０１０）／ｈ。氟康唑（三维）胶囊的相对生物利用度为９６％。差别无显著意义（Ｐ＞０．０５）。结论：氟康唑２种制剂在中国健康志愿者体内的药动学参数相似，具有生物等效性。     

Bioequivalence evaluation of two formulations of fluconazole 150 mg capsule in healthy Arab men

A randomized crossover study was conducted on 26 healthy Arab males to compare the bioavailability of two formulations of fluconazole 150 mg capsules, Fluconazole (test) and Diflucan (reference). The formulations were administered after an overnight fast with a washout period of 2 weeks. Twenty blood samples (per period) were collected over 168 h, plasma fluconazole concentrations were determined by locally validated high performance liquid chromatography (HPLC) assay and pharmacokinetic parameters were analysed by the standard non-compartmental method.The mean +/- SD maximum concentration (C(max)), time to reach maximum concentration (T(max)), area under the curve (AUC(0-->t) and AUC(0-->infinity)) and elimination half-life (t(1/2)) were 3.17+/-0.47 and 3.24+/-0.59 microg/ml, 2.62+/-2.01 and 2.65+/-1.63 h, 149.52+/-29.49 and 151.36+/-25.84 microg.h/ml, 163.57+/-29.9 and 164.89+/-26.46 microg.h/ml, and 36.81+/-5.72 and 36.56+/-5.36 h for the test and reference drug, respectively. These values are similar to previously reported values in other ethnic groups. The parametric 90% confidence intervals on the mean of the difference (test-reference) between the log-transformed values of the two formulations were 95.484% to 101.035%, 96.382% to 101.245% and 94.621% to 102.074% for AUC(0-->t), AUC(0-->infinity) and C(max), respectively. The results indicate that the two formulations are equivalent in the rate and extent of absorption. Further, a review of the literature indicates that there is no apparent ethnic variation in the absorption and elimination rates of fluconazole.     

小剂量氟康唑治疗慢性阻塞性肺疾病继发肺部真菌感染的回顾性分析

目的 探究对慢性阻塞性肺疾病（COPD）继发肺部真菌感染患者应用小剂量氟康唑的临床疗效分析。方法 选取2016年2月-2018年2月信阳市中心医院收治的COPD继发肺部感染患者共58例作为研究对象,随机分为观察组（29例）和对照组（29例）。对照组患者应用广谱抗菌药物及解痉平喘、雾化吸入糖皮质激素等治疗;观察组在对照组基础上应用小剂量氟康唑胶囊,100 mg/次,1次/d。两组治疗时间为2周。观察比较两组患者治疗效果,真菌清除情况及不良反应发生率。结果 治疗后,观察组总有效率为93.10%,显著高于对照组的68.97%,差异具有统计学意义（P<0.05）。治疗后,观察组和对照组患者真菌清除率分别为96.55%和62.07%,观察组真菌清除率明显高于对照组,且差异具有统计学意义（P<0.05）。观察组中出现1例胃肠道反应,而对照组中出现1例肝功能损害,1例皮疹,两组患者的不良反应发生情况无显著差异。结论 小剂量氟康唑对COPD继发肺部真菌感染疗效显著,不良反应较少,建议临床推广应用。     

The Design and Validation of a Novel Intravenous Microdialysis Probe: Application to Fluconazole Pharmacokinetics in the Freely-Moving Rat Model

Purpose. The purpose of this study was to design and validate a concentric, flexible intravenous microdialysis probe to determine drug concentrations in blood from the inferior vena cava of a freely-moving animal model. Methods. An intravenous microdialysis probe was constructed using fused-silica tubing and an acrylonitrile/sodium methallyl sulfonate copolymer hollow fiber. The probe was tested in vitro for the recovery of fluconazole and UK-54,373, a fluconazole analog used for probe calibration by retrodialysis. Subsequent in vivo validation was done in rats (n = 7) that had a microdialysis probe inserted into the inferior vena cava via the femoral vein, and the femoral artery was cannulated for simultaneous blood sampling. Comparisons of fluconazole pharmacokinetic parameters resulting from the two sampling methods were performed at 2 and 10 days after probe implantation. Results. There were no statistical differences between the microdialysis sampling and conventional blood sampling methods for the T_1/2, Cl, Vdss, and dose-normalized AUC by paired t-test (p > 0.05) for repeated dosing at day 2 and day 10 after probe placement. The probe recovery, as determined by retrodialysis, significantly decreased over the ten day period. This finding indicates the necessity for frequent recovery determinations during a long-term blood microdialysis experiment. Conclusions. These results show that microdialysis sampling in the inferior vena cava using this unique and robust probe design provides an accurate method of determining blood pharmacokinetics in the freely-moving rat for extended experimental periods. The probe design allows for a simple surgical placement into the inferior vena cava which results in a more stable animal preparation for long-term sampling and repeated-measures experimental designs.     

Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Influence of fluconazole on the pharmacokinetics of omeprazole was evaluated by single oral administration of omeprazole capsule 20 mg (control group), or single oral administration of fluconazole capsule, 100 mg, and omeprazole, 20 mg, after 4 days of daily oral administration of fluconazole, 100 mg (treated group), to 18 healthy male volunteers. Omeprazole is extensively metabolized in the liver through 5-hydroxylation and sulfoxidation reactions catalyzed predominantly by CYP2C19 and CYP3A4, respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. In treated group, the area under the plasma concentration-time curve of omeprazole from time zero to time infinity (AUC) was significantly greater (3090 vs 491 ng h/ml), terminal half-life of omeprazole was significantly longer (2.59 vs 0.85 h), and peak plasma concentration of omeprazole (C(max)) was significantly higher (746 vs 311 ng/ml) than that in control group. The greater AUC and higher C(max) in treated group could be due to inhibition of omeprazole metabolism by fluconazole.     

Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques

AIMS: To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques. METHODS: A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid. RESULTS: There was a lag-time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 +/- 1.19 microg ml(-1) in subcutaneous interstitial fluid and 3.58 +/- 0.14 microg ml(-1) in plasma. Subcutaneous interstitial fluid-to-plasma partition coefficient (Kp) of fluconazole was 1.16 +/- 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t-test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis sampling and those estimated using a blood flow-limited PBPK model. CONCLUSIONS: Microdialysis and suction blister techniques did not yield comparable results. It appears that microdialysis is a more appropriate technique for studying the rate of uptake of fluconazole into subcutaneous tissue. PBPK model simulation suggested that the distribution of fluconazole into subcutaneous interstitial fluid is dependent on tissue blood flow.     

The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole

AIMS: Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function. METHODS: In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively. RESULTS: Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated. CONCLUSIONS: The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at 相似文献