Antimicrob Agents Chemother. 2014 Dec;58(12):7510-9. doi: 10.1128/AAC.04108-14.

Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral nanoformulations.

 

Gautam N1, Puligujja P2, Balkundi S2, Thakare R1, Liu XM2, Fox HS2, McMillan J2, Gendelman HE2, Alnouti Y3.
  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
  • 2Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
  • 3Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA yalnouti@unmc.edu.

 

Abstract

The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.

PMID: 25288084

 

Supplements:

Even though there is still no cure for HIV, new antiretroviral therapies (ART) have markedly improved the prognosis of AIDS and could achieve life-long suppression of viral replication under detection limits in blood.   However, the need for life-long daily regimens, pill fatigue, co-morbid diseases, substance abuse, and ART interactions and side effects often lead to suboptimal adherence to ART. Loss of virologic control as a consequence of non-adherence to ART may lead to emergence of drug resistance, which compromises future treatment options. In addition under-treatment of HIV can trigger relapse and viral rebounds due to activation of latent virus hidden in anatomical and intracellular reservoirs including the lymph nodes. To address these limitations, long-acting nanoformulated ART (nanoART) approaches are developed for the sustained delivery of ART over long period of times with less frequent administration. nanoART is manufactured using nano-formulations made of polymers, excipients, and targeting moieties with optimum shape, size, and charge. This approach aims for cell-mediated drug delivery, where immunocytes uptake nanoART particles and serve as carriers to the targeted tissues. Drug is then slowly released from nanoART over prolonged period of times to maintain sustained, enhanced, and therapeutic levels of ART. In addition, nanoART uses immunocytes as a “Trojan horse” to deliver nanoART across barriers of viral sanctuaries, which are the source of viral rebounds.

 

 

YA fig1

Figure 1: Plasma concentration-versus-time profiles of ATV and RTV after single-dose administration in mice at 20 mg/kg (n=5).

 

In this study, the use of folic acid as a targeting moiety with nanoART resulted in plasma and tissue ART (ritonavir and atazanavir) concentrations in mice up to 200-fold higher compared to equimolar doses of native drug (Figure 1 and Figure 2). These tissues include hidden reservoirs for HIV such as the lymph nodes and brain, where ART is typically minimal. The enhanced pharmacokinetic profile of ART was associated with improved and sustained anti-HIV activity in humanized mice (Puligujja and others 2015). As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys without any systemic side effects.

If nanoART performs as well in humans, a once monthly or even one dose per 3 or 6 months with improved toxicity and adherence profiles and without compromising the efficacy could be accomplished. In addition, improving ART delivery to hidden viral sanctuaries may be able to eradicate the virus.

 

YA fig2

Figure 2: ATV and RTV concentration in (A) liver, and (B) lymph node after multiple dose administrations in mice at 20mg/kg (n=5)

 

References

Puligujja P, Arainga M, Dash P, Palandri D, Mosley RL, Gorantla S, Poluektova L, McMillan J, Gendelman HE. (2015). Pharmacodynamics of folic acid receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice. Antiviral Res, 120, 85-8.

 

 

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