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Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis

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Abstract

The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure–response–outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0.7–1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound sertraline concentrations is unlikely to reach MIC concentrations in the brain. Study findings also recommend against the use of higher doses of sertraline, especially those greater than the maximum FDA-approved daily dose (200 mg/day), since they unlikely provide any additional benefits and come with greater costs and risk of adverse events.

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Aknowledgements

This work was supported in part by the National Center for Advancing Translational Sciences of the National Institute of Health Award (Grant No. UL1TR000114), Fogarty International Center and National Institute of Neurologic Disorder and Stroke (Grant No. R01NS086312), and coin foundation fellowship supporting PhD students at Experimental and Clinical Pharmacology conducting research in infectious diseases. ASTRO-CM Team members: Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Carolyne Namuju, Alisat Sadiq, Kenneth Ssebambulidde, Reuben Kiggundu, Henry W Nabeta, Edward Mpoza, Andrew Akampurira, Tadeo Kiiza Kandole, Tony Luggya, Julian Kaboggoza, Eva Laker, Conrad Muzoora, Elissa K Butler, Jonathan Dyal, A. Wendy Fujita, Anna Stadelman, Alice Namudde, Ryan Halupnick, Bilal Jawed, Priya Vedula, Marnie Peterson, Kyle D Smith, Nathan C Bahr, Sruti S Velamakanni, James Fisher, Kirsten Nielsen, Bozena M Morawski, and Kathy Huppler Hullsiek.

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Authors and Affiliations

  1. Oncology Clinical Pharmacology, Pfizer Inc., 10555 Science Center Dr #2423C, La Jolla, San Diego, CA, 92121, USA

    Ali A. Alhadab

  2. Infectious Diseases Institute, Makerere University, Kampala, Uganda

    Joshua Rhein, Lillian Tugume, Abdu Musubire, Darlisha A. Williams, Mahsa Abassi & David B. Meya

  3. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    Joshua Rhein, Darlisha A. Williams, Mahsa Abassi, David B. Meya & David R. Boulware

  4. Department of Medicine, Makerere University, Kampala, Uganda

    Abdu Musubire & David B. Meya

  5. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Melanie R. Nicol & Richard C. Brundage

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  1. Ali A. Alhadab
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Alhadab, A.A., Rhein, J., Tugume, L. et al. Pharmacokinetics-pharmacodynamics of sertraline as an antifungal in HIV-infected Ugandans with cryptococcal meningitis. J Pharmacokinet Pharmacodyn 46, 565–576 (2019). https://doi.org/10.1007/s10928-019-09657-0

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