Sertraline Pharmacokinetics in HIV Ugandans with Cryptoccocal Meningitis

A. Alhadab, J. Rhein, R. Brundage K. Huppler Hullsiek, B. M. Morawski, M. L. Peterson, D. B. Meya, D. R. Boulwar

Author address: 

Univ. of Minnesota, Minneapolis, MN

Abstract: 

Background: 

Sertraline has shown fungicidal activity against Cryptococcus neoformans in vitro and in animal models. When combined with fluconazole, sertraline exhibits a synergistic effect. This study characterized the pharmacokinetics of sertraline when used as an adjunctive therapy to amphotericin B and fluconazole to treat cryptococcal meningitis in HIV-infected Ugandans. 

Methods: 

Sertraline plasma concentrations were measured in 111 patients from the ASTRO-CM trial by liquid chromatography/mass spectrometry (LC-MS-MS) on day 3, 7, 10 and 14 after daily doses of sertraline 100 to 400 mg PO added to standard induction therapy of amphotericin B (0.7 to 1.0 mg/kg/day) IV and fluconazole (800 to 1200 mg) PO. Nonlinear mixed effects analysis was performed to estimate the parameters of a one-compartment pharmacokinetic model using NONMEM software. The final model included patient weight that is scaled allometrically on clearance (CL/F) and volume of distribution (V/F). Missing weights were replaced with the population median value based on sex. The effect of anti-retroviral therapy (ART) (46 patients) and gender (73 males/38 females) on sertraline CL/F and V/F were tested as a fractional change using the likelihood ratio test (χ², α =0.5, df = 1). An age effect on CL/F and V/F was tested via linear, centered-linear and power models. 

Results: 

A one-compartment model with first-order absorption (fixed to 0.5 hr-1) and elimination adequately described the sertraline data. The population parameter estimates for CL/F and V/F were 54.9 L/h and 2830 L with 90.0% and 42.6% between subject variability, respectively. ART significantly increased CL/F by 89% with no effect on V/F. Neither sex nor age had an effect on CL/F or V/F. When compared to previously reported values in healthy volunteers, sertraline CL/F and V/F were lower in HIV-infected Ugandans with AIDS and exposure remained linearly proportional to dose, even when dosed higher than the daily maximum FDA recommended dose (200 mg/day). 

Conclusion:

Sertraline exhibits linear pharmacokinetics at doses higher than standard anti-depression dosing. ART significantly enhances sertraline clearance; however, the clinical significance of the ART-sertraline interaction remains to be determined, as does the relationship between sertraline exposure and fungal clearance rate.

abstract No: 

A-026
    • ICAAC 55th (2015)