دورية أكاديمية
Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.
| العنوان: | Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis. |
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| المؤلفون: | Stott KE; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Ahmadu A; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Kajanga C; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Moyo M; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.; Department of Medicine, Kamuzu University of Health Sciences, Blantyre, Malawi., Gondwe E; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Chimang'anga W; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Chasweka M; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi., Unsworth J; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Jimenez-Valverde A; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Jagota B; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Shah RV; Institute for Infection and Immunity, St George's University London, London, UK., Lawrence DS; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana., Lalloo DG; Liverpool School of Tropical Medicine, Liverpool, UK., Harrison T; Clinical Academic Group in Infection, St George's University Hospitals NHS Foundation Trust, London, UK.; MRC Centre for Medical Mycology, University of Exeter, Exeter, UK.; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK., Jarvis JN; Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.; Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana., Hope W; Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK., Mwandumba HC; Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.; Department of Medicine, Kamuzu University of Health Sciences, Blantyre, Malawi.; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK. |
| المصدر: | The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2023 Apr 03; Vol. 78 (4), pp. 1015-1022. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 7513617 Publication Model: Print Cited Medium: Internet ISSN: 1460-2091 (Electronic) Linking ISSN: 03057453 NLM ISO Abbreviation: J Antimicrob Chemother Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1997- : London : Oxford University Press Original Publication: London, New York, Academic Press. |
| مواضيع طبية MeSH: | Meningitis, Cryptococcal*/drug therapy , Meningoencephalitis*/drug therapy , Meningoencephalitis*/microbiology , Cryptococcus neoformans* , HIV Infections*/complications , HIV Infections*/drug therapy, Humans ; Adult ; Flucytosine ; Antifungal Agents/therapeutic use ; Bayes Theorem |
| مستخلص: | 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, 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). 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. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.) |
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| معلومات مُعتمدة: | RP-2017-08-ST2-012 United Kingdom DH_ Department of Health; MR/N023005/1 United Kingdom MRC_ Medical Research Council; G1001760 United Kingdom MRC_ Medical Research Council; 203919/Z/16/Z United Kingdom WT_ Wellcome Trust; MR/P020526/1 United Kingdom MRC_ Medical Research Council; MR/P006922/1 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | D83282DT06 (Flucytosine) 0 (Antifungal Agents) |
| تواريخ الأحداث: | Date Created: 20230301 Date Completed: 20230404 Latest Revision: 20240221 |
| رمز التحديث: | 20240221 |
| مُعرف محوري في PubMed: | PMC10068416 |
| DOI: | 10.1093/jac/dkad038 |
| PMID: | 36857467 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2091 |
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| DOI: | 10.1093/jac/dkad038 |