Journal Article

Lipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir

Sillman, Brady, Li, Wenkuan, Kulkarni, Tanmay A., Shetty, Bhagya L. Dyavar, Gautam, Nagsen, Alnouti, Yazen, Pan, Qiaoyu, McMillan, JoEllyn M., Szlachetka, Adam, Edagwa, Benson J., Smith, Nathan A., Gendelman, Howard E., Kumar, Devendra, Bade, Aditya N.

2021

نظرة عامة

A 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 advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility. Here, the authors provide a mechanism for an improved version of a nanoformulated myristoylated prodrug of cabotegravir (CAB), named NM2CAB, and its bioavailability, stability and pharmacokinetics in mice and rats performed in independent academic and a contracted research labs, suggesting that the extended half-life of the prodrug is not a property of enzymatic hydrolysis but rather release or dissolution of the prodrug from the nanocrystal.

• الناشر: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• موضوع: 13 / 13/51 / 14 / 14/63 / 631/154/152 / 631/154/309/152 / Animals / Antiretroviral drugs / Bioavailability / Disease transmission / Dissolution / Dosage / Drug Compounding / Drug development / Drug Liberation / Emtricitabine / Endocytosis / Half-life / HIV / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Hydrolysis / Kinetics / Laboratories / Lipids - chemistry / Lipophilic / Lymphoid tissue / Macrophages / Male / Mice / Mice, Inbred BALB C / multidisciplinary / Muscles / Nanocrystals / Nanoparticles - chemistry / pH effects / Pharmacokinetics / Pharmacology / Prodrugs / Prodrugs - pharmacology / Pyridones - administration & dosage / Pyridones - blood / Pyridones - pharmacokinetics / Rats / Rats, Sprague-Dawley / Reproducibility / Reproducibility of Results / Science / Science (multidisciplinary) / Tenofovir / Tissue Distribution