Background
Approximately 58 million people are chronically infected with HCV globally, with approximately 1.5 million new infections per year and a disproportionate burden in low- and middle-income countries. Approved oral treatments, administered over 8 – 12 weeks, are highly effective demonstrating >98% sustained virological response (SVR) in RCTs. However, in some populations intention to treat analyses have indicated SVR rates <50%. Long-acting drug delivery in HCV holds promise to reduce loss of patients to follow-up, mitigate resistance and adherence challenges, and facilitate test and cure strategies. Surveys of patient and provider groups have consistently demonstrated high potential acceptability of such an approach.
Methods
Glecaprevir and pibrentasvir were formulated using a spray drying technology and processed to form a 11 mm x 2 mm solid using vacuum compression moulding. Resultant solid injectable formulations were administered to Male Sprague Dawley rats (n = 4, 250-300g) within each flank of the scapular region using a 12-gauge needle. Each solid consisted of 30 wt% glecaprevir, 30 wt% pibrentasvir, and 40% excipient. Total dose was 27mg for each drug. Whole blood was collected from the tail vein over 13 weeks and following processing, drug concentrations were quantified in plasma using a validated LC MS/MS assay.
Results
Following administration, Cmax concentrations of 2490 ± 500 ng / mL glecaprevir and 248 ± 46 ng / mL pibrentasvir were achieved. Tmax occurred at ~2 hours post dose for glecaprevir and ~10 hours post dose for pibrentasvir. AUC0-8weeks was 169 ± 69 μg·h/ml for glecaprevir and 47.3 ± 6.6 μg·h/ml for pibrentasvir. Both drugs remained detectable within plasma for the full 13 weeks. No behavioural issues were encountered, animals gained weight throughout and no overt injection site issues were visible upon inspection.
Conclusions
Preclinical data for a novel glecaprevir / pibrentasvir solid injectable demonstrated sustained concentrations of both drugs in rats for greater than 8 weeks. High concentrations were achieved rapidly after administration possibly mitigating the need for oral lead-in which would be sub-optimal for treatment of chronic infection. Further work is required to understand variability in pharmacokinetic exposure of solid injectables relative to their liquid counterparts, and acceptability of the solid injectable approach to patients.
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