RT Journal Article
SR Electronic
T1 Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.18.427147
DO 10.1101/2021.01.18.427147
A1 Nagsen Gautam
A1 JoEllyn M. McMillan
A1 Devendra Kumar
A1 Aditya N. Bade
A1 Qiaoyu Pan
A1 Tanmay A. Kulkarni
A1 Wenkuan Li
A1 Nathan A Smith
A1 Bhagya L. Dyavar Shetty
A1 Brady Sillman
A1 Adam Szlachetka
A1 Benson J. Edagwa
A1 Howard E. Gendelman
A1 Yazen Alnouti
YR 2021
UL http://biorxiv.org/content/early/2021/01/19/2021.01.18.427147.abstract
AB A single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.Competing Interest StatementBenson Edagwa and Howard E. Gendelman are cofounders of Exavir Therapeutics, Inc. and are inventors on a patent that cover yearlong integrase inhibitor prodrug formulations (PCT/US2019/057406, WO2020-086555).