College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Antimicrob Agents Chemother. 2018 Jul 27;62(8). doi: 10.1128/AAC.00464-18. Print 2018 Aug.
The pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood ( = 11) and urine ( = 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum () = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time to () = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (/) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CL) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life () = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%; < 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.).
在 18 名健康成年受试者中评估了两种重复剂量的口服磷霉素氨丁三醇的药代动力学（PK）、安全性和耐受性。受试者接受 3 g 隔日（QOD）给药 3 剂，然后每日（QD）给药 7 剂，或者相反，在一项 I 期、随机、开放标签、两周期交叉研究中。在第 1 天和第 5 天给药前和给药后 24 小时内采集了（= 11）和尿液（= 4 个采集间隔）的连续血样，并在第 3 天和第 7 天采集了预剂量浓度。在各自的 QOD 和 QD 给药方案中，第 5 天的 PK 参数在第 1 天和第 5 天内相似，且方案间也相似。第 5 天 QOD 和 QD 给药方案时磷霉素在血浆中的平均（±标准偏差 [SD]）PK 参数如下：血清中药物的最大浓度（）= 24.4 ± 6.2 与 23.8 ± 5.6 μg/ml，达峰时间（）= 2.2 ± 0.7 与 2.0 ± 0.4 h，表观分布容积（/）= 141 ± 67.9 与 147 ± 67.6 升，表观清除率（CL/）= 21.4 ± 8.0 与 20.4 ± 5.3 升/小时，肾清除率（CL）= 7.5 ± 4.1 与 7.3 ± 3.5 升/小时，0 至 24 小时浓度-时间曲线下面积（AUC）= 151.6 ± 35.6 与 156.6 ± 42.5 μg·h/ml，消除半衰期（）= 4.5 ± 1.1 与 5.0 ± 1.7 h。尿液浓度在 0 至 8 小时的尿液采集间隔内达到约 600 μg/ml，但个体间差异很大。大约 35%至 40%的 3 g 剂量在给药后 24 小时内通过尿液排泄。在这项研究中没有发现新的安全性问题。与 QOD 方案相比，QD 方案的无腹泻天数显著降低（61%比 77%；< 0.0001）。需要进一步的研究来确定口服磷霉素氨丁三醇重复剂量方案的临床获益/风险比。（本试验在 ClinicalTrials.gov 注册，注册号为 NCT02570074。）
