Abstract
ABSTRACTThere is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.
Highlights
Cryptococcal meningitis is a leading infectious cause of morbidity and mortality worldwide, with approximately 223,100 incident cases and 181,100 deaths annually [1]
A meta-analysis of clinical trials of DAmB monotherapy was performed to estimate the contribution of various DAmB dosages to the observed heterogeneity in study outcomes
Monte Carlo simulations were performed to estimate the mean, median, and dispersion values corresponding to drug exposures that are associated with microbiological and clinical outcomes of DAmB monotherapy
Summary
Cryptococcal meningitis is a leading infectious cause of morbidity and mortality worldwide, with approximately 223,100 incident cases and 181,100 deaths annually [1]. Given the paucity of new agents, one important strategy for improving clinical outcomes is a better understanding and use of currently available compounds. Amphotericin B deoxycholate (DAmB) is the most potent formulation of AmB on a milligram-to-milligram basis [9, 10] and is a mainstay for the treatment of cryptococcal meningitis. Clinical studies have progressively examined escalating dosages of 0.4 mg/kg of body weight every 24 h (q24h) [11, 12], 0.7 mg/kg q24h [13,14,15], and 1.0 mg/kg q24h [5] of DAmB for cryptococcal meningitis. A meta-analysis of clinical trials of DAmB monotherapy was performed to estimate the contribution of various DAmB dosages to the observed heterogeneity in study outcomes. Monte Carlo simulations were performed to estimate the mean, median, and dispersion values corresponding to drug exposures that are associated with microbiological and clinical outcomes of DAmB monotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
