Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis

被引:5
作者
Stott, Katharine E. [1 ,2 ]
Ahmadu, Ajisa [2 ]
Kajanga, Cheusisime [2 ]
Moyo, Melanie [2 ,3 ]
Gondwe, Ebbie [2 ]
Chimang'anga, Wezzie [2 ]
Chasweka, Madalitso [2 ]
Unsworth, Jennifer [1 ]
Jimenez-Valverde, Ana [1 ]
Jagota, Bhavana [1 ]
Shah, Reya, V [4 ]
Lawrence, David S. [5 ,6 ]
Lalloo, David G. [7 ]
Harrison, Tom [8 ,9 ,10 ]
Jarvis, Joseph N. [5 ,6 ]
Hope, William [1 ]
Mwandumba, Henry C. [2 ,3 ,10 ]
机构
[1] Univ Liverpool, Dept Mol & Clin Pharmacol, Antimicrobial Pharmacodynam & Therapeut, Liverpool, England
[2] Malawi Liverpool Wellcome Trust Clin Res Programme, Blantyre, Malawi
[3] Kamuzu Univ Hlth Sci, Dept Med, Blantyre, Malawi
[4] St Georges Univ London, Inst Infect & Immun, London, England
[5] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London, England
[6] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana
[7] Univ Liverpool Liverpool Sch Trop Med, Liverpool, England
[8] St Georges Univ Hosp NHS Fdn Trust, Clin Acad Grp Infect, London, England
[9] Univ Exeter, MRC Ctr Med Mycol, Exeter, England
[10] Univ Liverpool Liverpool Sch Trop Med, Dept Clin Sci, Liverpool, England
基金
英国惠康基金;
关键词
LIPOSOMAL AMPHOTERICIN-B; 5-FLUOROCYTOSINE; MENINGITIS; PHARMACODYNAMICS; RESISTANCE; TOXICITY;
D O I
10.1093/jac/dkad038
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Background 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. Methods 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. Results 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, AUC(24) 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 AUC(24) was 0.69 (IQR 0.58-0.82). Conclusions 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.
引用
收藏
页码:1015 / 1022
页数:8
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