Preclinical pharmacokinetics of novel long-acting tenofovir alafenamide/bictegravir solid injectable in rats

Abstract

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Preclinical pharmacokinetics of novel long-acting tenofovir alafenamide/bictegravir solid injectable in rats

Usman Arshad^1,2, Eleanor Barlow^2,3, Helen Cox^1,2, Joanne Sharp^1,2, Henry Pertinez^1,2, Joanne Herriott^1,2, Edyta Kijak^1,2, Eduardo Gallardo-Toledo^1,2, James Hobson^2,3, Andrew Dwyer^2,3, Jonathan Massam^2,3, 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); ³Department of Chemistry, University of Liverpool

Background: Tenofovir alafenamide (TAF) is a nucleoside reverse transcriptase inhibitor approved for the treatment of HIV in combination with bictegravir (BIC), an integrase strand transfer inhibitor, and emtricitabine. Daily oral treatment and pre-exposure prophylaxis are highly effective when taken as prescribed. However, inadequate adherence to oral products reduces effectiveness. Another integrase inhibitor, cabotegravir, has been demonstrated to be effective in pre-exposure prophylaxis and is available clinically as a long-acting (LA) injectable. This work describes preclinical pharmacology of a novel TAF/BIC LA solid injectable.

Material and methods: TAF and BIC formulations were manufactured using emulsion-templated freeze-drying and processed into a compressed solid using vacuum compression moulding (VCM). Male Sprague Dawley rats (n = 4, 250-300 g) were administered a single TAF and single BIC subcutaneous implant (2 × 8 mm) in the scapular region using a 12-G needle. The implant formulations consisted of 70 wt% BIC or TAF and 30 wt% PVA (24 mg of each drug). Plasma samples were collected from the lateral tail vein throughout a 13-week period. Tenofovir (TFV) and BIC concentrations were quantified in plasma using liquid chromatography–tandem mass spectrometry (LC-MS/MS).

Results: Dispersion of formulations in water yielded TAF or BIC particles with 100–250 nm and 700–850 nm z-average diameters, respectively, as measured by dynamic light scattering. TFV plasma concentrations remained above the human C_trough for 7 days and calculated parameters were as follows; a C_max of 2681 ng/mL, Tmax of 6 h and AUC_0-tlast of 59.6 μg.h/mL and T1/2 of 2.1 days. Plasma BIC concentrations exceeded the human oral steady-state C_trough within 3 h of administration and remained above this for 84 days (C_max of 33 777 ng/mL, T_max = 1 day, AUC_0-tlast = 17 669 μg.h/mL, T1/2 of 31 days). No behavioural issues were encountered, animals gained weight throughout, and no overt implant-site reactions were observed.

Conclusions: Preclinical data for a novel TAF and BIC solid injectable demonstrated sustained concentrations in rats over a period of 7 and 84 days, respectively. Assessment of TAF pharmacokinetics in rats is complicated by species-specific metabolisms preventing assessment of TAF itself. Since benefits of TAF over TFV are derived from augmented intracellular permeation, further investigation of TAF PK is needed in a species more representative of human metabolism. Further work is required to optimize the implant pharmacokinetics and formally assess injection site safety, which has been an issue for other LA approaches for TFV prodrugs.