Journal Article

A year-long extended release nanoformulated cabotegravir prodrug

Sillman, Brady, Yue, Tai-Yuen, Kulkarni, Tanmay A., Domanico, Paul L., Mosley, R. Lee, Gautam, Nagsen, Fox, Howard S., Alnouti, Yazen, Szlachetka, Adam, McMillan, JoEllyn M., Shetty, Bhagya Laxmi Dyavar, Sravanam, Sruthi, Morsey, Brenda M., Moore, Gary, Edagwa, Benson J., Gendelman, Howard E., Lamberty, Benjamin G., Wojtkiewicz, Melinda S., Meza, Jane, Bade, Aditya N., Hilaire, James R.

2020

Overview

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB’s effectiveness. Nanoformulated long-acting cabotegravir prodrugs are shown to be capable of extending the native drug’s antiretroviral activity, biodistribution and pharmacokinetics for up to 12 months in mice and rhesus macaques.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/1435 / 631/154/152 / 631/154/309 / 631/154/433 / 631/154/436 / Animals / Anti-Retroviral Agents - metabolism / Anti-Retroviral Agents - pharmacology / Anti-Retroviral Agents - toxicity / Antiretroviral agents / Antiretroviral drugs / Barriers / Biocompatibility / Biological Transport / Biomaterials / Body weight / Carbon / Chemical compounds / Chemistry and Materials Science / Condensed Matter Physics / Cytotoxicity / Delayed-Action Preparations / Drug Compounding / Drug delivery systems / Drug Interactions / Drug Stability / Drugs / Fatty acids / Injection / Materials Science / Mice / Molecular chains / Nanocrystals / Nanostructures - chemistry / Nanotechnology / Optical and Electronic Materials / Pharmacokinetics / Pharmacology / Poloxamers / Prodrugs - chemistry / Prodrugs - metabolism / Pyridones - metabolism / Pyridones - pharmacology / Pyridones - toxicity / Toxicity