Chu Wan-Yu, Fahal Ahmed H, Ahmed Eiman Siddig, Bakhiet Sahar Mubarak, Bakhiet Osama Elhadi, Fahal Lamis Ahmed, Mohamed Abubakar Ahmed, Mohamedelamin El Sammani Wadaa, Bahar Mustafa El Nour, Attalla Hadil Yassir, Siddig Emmanuel Edwar, Mhmoud Najwa A, Musa Ahmed Mudawi, Oyieko Peelen, Egondi Thaddaeus, Brüggemann Roger J, Hata Katsura, Strub-Wourgaft Nathalie, Alves Fabiana, Nyaoke Borna A, Zijlstra Eduard E, Dorlo Thomas P C
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Infect Dis. 2025 Sep 15;232(3):e518-e528. doi: 10.1093/infdis/jiaf279.
The first clinical trial on eumycetoma was recently conducted in Sudan, comparing oral fosravuconazole, prodrug of active ravuconazole, with the standard-of-care oral itraconazole. Building on this trial, the present study aimed to characterize the pharmacokinetics-pharmacodynamics (PK-PD) of ravuconazole, itraconazole, and hydroxyitraconazole in patients with eumycetoma and guide selection of either a 200-mg or 300-mg dose of fosravuconazole.
Nonlinear mixed-effects modeling was used to develop population PK models in 52 patients receiving 3 daily loading doses followed by weekly fosravuconazole (200 mg or 300 mg) or twice-daily itraconazole (total 400 mg), both over 12 months. Attainment of the in vitro 90% minimum inhibitory concentration (MIC90) for Madurella mycetomatis was assessed, and the relationships between drug exposure, lesion size reduction, and complete cure were evaluated.
Ravuconazole PK followed a 2-compartment model with Michaelis-Menten elimination and a 63% (95% confidence interval, 38%-90%) bioavailability increase during the loading phase, leading to 75% higher exposure for a 50% dose increase. Itraconazole and hydroxyitraconazole were modeled jointly, with autoinhibition of itraconazole metabolism. Free ravuconazole remained above the MIC90 throughout the entire 12-month treatment period, while free itraconazole never reached the MIC90. Despite a large range in antifungal exposure, no significant relationships were found between drug exposure and lesion size reduction or complete cure, indicating no additional benefit of 300 mg over 200 mg fosravuconazole.
Ravuconazole and itraconazole showed nonlinear clearance with no clear exposure-response relationship. The 200 mg fosravuconazole dose is preferred for future use over 300 mg, as it lowers pill burden and enhances cost-effectiveness. Clinical Trials Registration. NCT03086226.
最近在苏丹进行了首例关于足菌肿的临床试验，比较了活性药物雷夫康唑的前体药物口服福沙康唑与标准治疗药物口服伊曲康唑。基于该试验，本研究旨在描述雷夫康唑、伊曲康唑和羟基伊曲康唑在足菌肿患者中的药代动力学-药效学（PK-PD）特征，并指导选择200毫克或300毫克剂量的福沙康唑。
采用非线性混合效应模型，在52例患者中建立群体PK模型，这些患者接受3次每日负荷剂量，随后每周服用福沙康唑（200毫克或300毫克）或每日两次伊曲康唑（总量400毫克），持续12个月。评估对马杜拉足菌肿体外90%最低抑菌浓度（MIC90）的达到情况，并评估药物暴露、病变大小缩小和完全治愈之间的关系。
雷夫康唑的PK遵循二室模型，具有米氏消除，在负荷阶段生物利用度增加63%（95%置信区间，38%-90%），导致剂量增加50%时暴露量增加75%。伊曲康唑和羟基伊曲康唑联合建模，存在伊曲康唑代谢的自身抑制。在整个12个月的治疗期间，游离雷夫康唑始终保持在MIC90以上，而游离伊曲康唑从未达到MIC90。尽管抗真菌暴露范围很大，但未发现药物暴露与病变大小缩小或完全治愈之间存在显著关系，表明300毫克福沙康唑并不比200毫克有额外益处。
雷夫康唑和伊曲康唑显示出非线性清除，无明确的暴露-反应关系。未来使用时，200毫克福沙康唑剂量优于300毫克，因为它降低了药丸负担并提高了成本效益。临床试验注册。NCT03086226。
