Population pharmacokinetic model and meta-analysis of outcomes of amphotericin B deoxycholate use in adults with cryptococcal meningitis

Journal article

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis (CM). A PK study was conducted in n=42 patients receiving DAmB 1 mg/kg 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 CM patients treated with DAmB monotherapy and a meta-analysis was performed.

The PK parameter means (standard deviation) were: clearance, 0.03 (0.01) x weight + 0.95 (0.02) litres/hour; volume, 0.89 (0.90) x weight + 1.54 (1.13) litres; first-order rate constant from central to peripheral compartment, 7.12 (6.50) hours^-1; from peripheral to central compartment, 12.13 (12.50) hours^-1. The meta-analysis suggested that DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility, but not in mortality outcomes. Simulations of area under concentration-time curve (AUC144-168) resulted in median (interquartile range) values 5.83 mg.h/litre (4.66-8.55), 10.16 (8.07- 14.55) and 14.51 (11.48-20.42), 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 on clearance and volume. Inter-patient PK variability is modest and unlikely to be responsible for variability in clinical outcome. There is a discord between the impact that drug exposure has on CSF sterility and on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

Authors: Stott, K; Beardsley, J; Whalley, S; Kibengo, F; Mai, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Microbiology
• Journal: Antimicrobial Agents and Chemotherapy
• Volume: 62
• Issue: 7
• Pages: e02526-17
• Publication date: 2018-05-07
• Acceptance date: 2018-04-27
• DOI: 10.1128/AAC.02526-17
• EISSN: 1098-6596
• ISSN: 0066-4804
• Keywords: pharmacodynamics; cryptococcal meningitis; pharmacokinetics; amphotericin B deoxycholate