Pharmacokinetic testing of a first-generation cabotegravir prodrug in rhesus macaques

Abstract

Long-acting antiretrovirals can improve therapy and prevention for HIV-1 infection. Current longacting cabotegravir (CAB LAP) can be administered every other month. Previously, we demonstrated that a myristoylated CAB prodrug encased in poloxamer 407 provided extended plasma drug concentrations. We now demonstrate that this first-generation nanoformulated prodrug can sustain plasma CAB concentrations above the PA-IC 90 for four months in rhesus macaques. A 2.5-fold extension in CAB half-life and a 1.6-fold increase in area under the concentration-time curve were observed compared to CAB LAP.

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice

“…The sustained human grafts as confirmed by flow cytometry were viable and functional for more than 6 months, which provided a platform that allowed treatment interventions for prolonged time periods and a clear ability during ART to best establish a continuous latent HIV-1 reservoir in peripheral tissues and the brain and the noted immunological responses to the viral infection 12,17,29,36,37,39 . These previously published data support the successful use of humanized mice in studies of HIV/AIDS pathogenesis, therapeutics 40–42 , and treatment 12–14,16,18,29,43,44 . These studies, taken together, clearly provide a rationale for the scientific approaches taken in the current report 12,13,29,43,45–47 .…”

“…Therefore, our approaches towards evaluating viral cures have included the demonstrated ability of the drugs to reach sites of latent infection and to do so at significant levels 18,37,39,43,44 . Notably, the use of molecular tools can permanently eliminate the viral genome and preclude reactivation 20,21,24,48 .…”

The Promise of Long-Acting Antiretroviral Therapies: From Need to Manufacture

“…NMDTG injection of (118 mg/mL; 25.5 mg/kg DTG equivalents) to rhesus macaques resulted in plasma DTG levels of up to 86 and 28 ng/mL on days 35 and 91 [21] without adverse events [17,21]. Similarly, parenteral nanoformulated CAB prodrug administration of 45 mg/kg equivalents provided plasma drug levels above 4 times the PA-IC 90 (660 ng/mL) for 56 days in rhesus macaques and above the 1X PA-IC 90 (166 ng/ml) to 13 weeks in mice [18,22].…”

“…Indeed, the structural and chemical complexity of nanomedicines can affect scale-up production, batch-to-batch reproducibility, formulation stability and sterilization [101,110,111]. With these hurdles in mind protocols for scale-up and formulation reproducibility were developed for LASER ART then tested in large animals for long-acting activity and toxicities [21,22,24]. GLP protocols ensured uniformity, consistency, reliability, reproducibility, quality, and integrity of pharmaceutical products ii .…”

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges

“…Agarwal et al showed that the fatty acid prodrugs of FTC [ 68 ] and 3TC [ 69 ] improved anti-HIV activity and cellular uptake. Other examples in this category include fatty acid conjugates of CAB [ 70 ] and dolutegravir (DTG) [ 71 ], later developed as LA injectable poloxamer nanocrystal formulations [ 72 , 73 ]. The palmitic acid prodrug of DTG has been formulated into biodegradable microparticles [ 74 ], and PK evaluation in rabbits (SC injection, 30 mg/kg) showed that the IC 90 of DTG was maintained for >3 months.…”