Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection

Abstract

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.

Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis

“…After subcutaneous administration and during the first passage, DcNP particles are shown to track preferentially into the lymph, but not blood capillaries, as observed with a near-infrared fluorophore (indocyanine green) tagged DcNP in mice [29]. In addition, DcNP has enabled the maintenance of cellular drug levels in lymph node mononuclear cells (above plasma drug levels) for over 2-4 weeks in non-human primates (NHP) [9,10]. In our current report, we were able to demonstrate less dramatic long-acting effects due to DcNP for GT combinations when given in an IV dosage form.…”

“…As lymphatic cancer invasion is believed to be an early site for metastasis, it is possible that DcNP loaded drugs may provide additional benefits. With at least 4 sets of HIV drug combinations formulated in DcNP, all drugs have been given subcutaneously in DcNP dosage for each composition into lymphatics in their first-pass [8][9][10][11]29]. After subcutaneous administration and during the first passage, DcNP particles are shown to track preferentially into the lymph, but not blood capillaries, as observed with a near-infrared fluorophore (indocyanine green) tagged DcNP in mice [29].…”

“…In developing long-acting (LA) and combination anti-retroviral (drug) therapeutics or cART, our laboratory has discovered a simple, scalable technology that enables the incorporation of 2-3 HIV drugs that are water insoluble such as lopinavir, ritonavir, atazanavir, and efavirenz together with water soluble tenofovir and lamivudine [8][9][10][11]. This drug-combination nanoparticle (DcNP) technology has proven to be a platform that allows high loading of both hydrophobic and hydrophilic HIV drugs.…”

“…This drug-combination nanoparticle (DcNP) technology has proven to be a platform that allows high loading of both hydrophobic and hydrophilic HIV drugs. With at least 4 different sets of cART tested in non-human primates, DcNP enhances lymphoid tissue and cell drug accumulation while exhibiting long-acting cellular exposure [8][9][10][11]. With this novel enabling technology, we have investigated whether gemcitabine (G, soluble) and paclitaxel (T, insoluble) can be assembled into a drug-combination particle able to enhance pharmacokinetics and also inhibit the growth of metastatic breast cancer.…”

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“…maintaining high levels of the antiviral drugs in tissues, with reduced dose frequency. For instance, Kaletra in its oral formulation requires daily administration due to its rapid clearance, but data produced from nonhuman primates have demonstrated that the equivalent mass of one pill of Kaletra formulated as a lipid-nanoparticle for subcutaneous administration achieves approximately 10-fold higher concentrations in lymph nodes for about one week [10]. Similarly, the lipid-nanoparticle encapsulation of tenofovir, a nucleotide analogue used to treat HIV and hepatitis B infection that has some structural and functional similarities with remdesivir, has also been shown to enhance tissue concentrations and prolong retention of its active phosphorylated moieties in nonhuman primate studies [11].…”