Optimisation and validation of a sensitive bioanalytical method for niclosamide

Abstract

The SARS-CoV-2 pandemic has spread at an unprecedented rate, and repurposing opportunities have been intensively studied with only limited success to date. If successful, repurposing will allow interventions to become more rapidly available than development of new chemical entities. Niclosamide has been proposed as a candidate for repurposing for SARS-CoV-2 based upon the observation that it is amongst the most potent antiviral molecules evaluated in vitro. To investigate the pharmacokinetics of niclosamide, reliable, reproducible and sensitive bioanalytical assays are required. Here, a liquid chromatography tandem mass spectrometry assay is presented which was linear from 31.25-2000 ng/mL (high dynamic range) and 0.78-100 ng/mL (low dynamic range). Accuracy and precision ranged between 97.2% and 112.5%, 100.4% and 110.0%, respectively. The presented assay should have utility in preclinical evaluation of the exposure-response relationship and may be adapted for later evaluation of niclosamide in clinical trials.

Scalable nanoprecipitation of niclosamide and in vivo demonstration of long-acting delivery after intramuscular injection

“…Plasma concentrations were determined using a validated liquid chromatography mass spectrometry method. 36 Plasma PK data was fitted with an empirical biexponential model with first order input as a convenience function to provide a summary description of the PK profiles as a function of dose and give parameter estimates for the half-lives of the exponential phases, area under the curve (AUC) and apparent clearance. Model fitting was carried out via nonlinear regression in the R programming environment (v 4.0.3), Fig.…”