Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats

2

Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats

Eduardo Gallardo-Toledo^1,2, Usman Arshad^1,2, Henry Pertinez^1,2, Joanne Sharp^1,2, Joanne Herriott^1,2, Edyta Kijak^1,2, Helen Cox^1,2, Alison Savage^2,3, Catherine Unsworth^2,3, Andrew Dwyer^2,3, James Hobson^2,3, Lee Tatham^1,2, David Thomas⁴, Paul Curley^1,2, Steve Rannard^2,3 and Andrew Owen^1,2

¹Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool; ²Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool; ³Department of Chemistry, University of Liverpool; ⁴Department of Infectious Diseases, John's Hopkins University School of Medicine

Background: Glecaprevir (G) and pibrentasvir (P) is a fixed-dose combination (FDC) approved to treat all six types of hepatitis C. However, patient adherence to oral treatment regimens remains a major challenge with considerably lower efficacy in clinical use than reported in RCTs. Long-acting injectables (LAI) could address poor adherence through long-term exposure of both G and P after a single administration.

Materials and methods: Male Sprague Dawley rats (n = 4 per group) were intramuscularly dosed into both thighs with LAI suspensions of G and P alone and both drugs in an FDC (GP-FDC, 1:1 ratio) as follows: GP-FDC group (75 mg G + 75 mg P, 150 μL/thigh), G group (150 mg G, 150 μL/thigh), P group (150 mg P, 150 μL/thigh) and GP group (75 mg G, 150 μL/left thigh + 75 mg P, 150 μL/right thigh). A second set of experiments evaluated the effects of different GP-FDC active doses (18.75, 37.5 and 75 mg) on the pharmacokinetics (PK) by changing the dosing volume (0.075, 0.15 and 0.3 mL of GP-FDC at 500 mg/mL) or GP-FDC suspension strength (0.3 mL of GP-FDC at 125, 250 and 500 mg/mL). For all studies, blood samples were collected from the lateral tail vein up to 90 days' post-dose. G and P concentrations were quantified in plasma using a validated method by LC-MS/MS.

Results: GP-FDC showed plasma concentration–time profiles above the reported median human C_trough for both G and P over the 90 days. However, for single drug-LAI suspensions, plasma concentrations of P were above the human Ctrough over 70 days for both P alone and GP groups, whereas a more rapid drop in plasma concentrations were observed for G in both G and GP groups, after 35 and 28 days, respectively. In the second set of experiments, a linear dose-dependent PK was observed with increasing volume, with a proportional increase in the AUC_0-tlast for both G and P (G: 106, 220 and 390 μg·h/mL and P: 157, 346 and 513 μg·h/ml for 0.075, 0.15 and 0.3 mL, respectively). Conversely, when dose was titred by GP-FDC suspension strength, a non-dose linear increase in the AUC0-tlast for both G and P was observed (G: 156, 325 and 390 μg·h/mL and P: 200, 400 and 513 μg·h/mL for 125, 250 and 500 mg/mL). Notwithstanding, both experimental conditions provided appropriate plasma exposures; while the 18.75 mg dose maintained G and P exposure above the human C_trough for 5 and 11 weeks, respectively, the 37.5 and 75 mg doses maintained plasma exposures above the human C_trough for both G and P throughout the 90 days.

Conclusions: Plasma exposure of both G and P between GP-FDC and single drug-LAI suspensions suggested that P helps to maintain a longer terminal half-life for G. Moreover, PK data demonstrate a sustained exposure over a period of 90 days for both G and P in rats when novel GP-FDC is administered. Optimization of drug ratios, as well as GLP toxicology assessments, is required to progress to human clinical trials.