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.
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.
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).
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.
- ICAAC 55th (2015)