TY - JOUR
T1 - A year-long extended release nanoformulated cabotegravir prodrug
AU - Kulkarni, Tanmay A.
AU - Bade, Aditya N.
AU - Sillman, Brady
AU - Shetty, Bhagya Laxmi Dyavar
AU - Wojtkiewicz, Melinda S.
AU - Gautam, Nagsen
AU - Hilaire, James R.
AU - Sravanam, Sruthi
AU - Szlachetka, Adam
AU - Lamberty, Benjamin G.
AU - Morsey, Brenda M.
AU - Fox, Howard S.
AU - Alnouti, Yazen
AU - McMillan, Jo Ellyn M.
AU - Mosley, R. Lee
AU - Meza, Jane
AU - Domanico, Paul L.
AU - Yue, Tai Yuen
AU - Moore, Gary
AU - Edagwa, Benson J.
AU - Gendelman, Howard E.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41563-020-0674-z
DO - 10.1038/s41563-020-0674-z
M3 - Article
C2 - 32341511
AN - SCOPUS:85084132874
SN - 1476-1122
VL - 19
SP - 910
EP - 920
JO - Nature Materials
JF - Nature Materials
IS - 8
ER -