Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.
Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.
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DOI：
10.1093/jac/dkad038
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发表时间：
2023-04-03
影响因子：
5.2
通讯作者：
Mwandumba, Henry C.
中科院分区：
文献类型：
--
作者：
Stott, Katharine E.;Ahmadu, Ajisa;Kajanga, Cheusisime;Moyo, Melanie;Gondwe, Ebbie;Chimang'anga, Wezzie;Chasweka, Madalitso;Unsworth, Jennifer;Jimenez-Valverde, Ana;Jagota, Bhavana;Shah, Reya, V;Lawrence, David S.;Lalloo, David G.;Harrison, Tom;Jarvis, Joseph N.;Hope, William;Mwandumba, Henry C.
描述临床氟胞嘧啶药代动力学（PK）的数据有限。氟胞嘧啶分配至CNS的变异性尚不清楚。我们描述了HIV相关隐球菌脑膜脑炎患者氟胞嘧啶PK的个体间变异性。此外，我们定量了氟胞嘧啶CSF分配的程度和变异性。在马拉维布兰太尔的64例确诊HIV相关隐球菌脑膜脑炎患者中进行了一项PK研究。开发了四室PK模型，并对不同剂量和不同给药方案的氟胞嘧啶进行了Monte Carlo模拟。中央室的估计平均表观容积为17.50（SD 9.99）L;平均表观清除率为5.88（SD 3.35）L/h; CNS室的平均表观容积为41.73（SD 13.66）L。根据贝叶斯后验估计值，25 mg/kg q6 h剂量下稳态（144-168 h）时血浆AUC 24值的中位数（IQR）为890.38（603.81-1213.70）mg.h/L，CSF为595.66（425.69-776.64）mg.h/L。CSF：血浆AUC 24的比值为0.69（IQR 0.58-0.82）。本研究揭示了HIV相关隐球菌脑膜脑炎患者血浆和CSF中氟胞嘧啶PK的显著个体间变异性。群体PK模型是修订氟胞嘧啶方案的第一个关键步骤，该方案可最大限度地杀灭真菌，并最大限度地减少毒性和耐药性的出现。
There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144–168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81–1213.70) mg.h/L in plasma and 595.66 (425.69–776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58–0.82). This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.
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影响因子：
4.9
作者：
BLOCK, ER;BENNETT, JE
通讯作者：
BENNETT, JE
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