Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation

Abstract

Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs-hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)-stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long-acting pharmacokinetics for all three drugs. In addition, the lymphocyte-targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation.

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

“…This combination was dubbed "the targeted, long-acting and combination anti-retroviral therapy" (TLC-ART). The main findings were enhanced and showed persistent drug levels throughout the body of NHPs for over a week [114], and importantly not exclusively in the draining, sentinel lymph nodes [110,112,116]. However, more research is needed in order to fully understand how compounds are retained intra-lymphatically.…”

Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy

“…While the exact physiological mechanisms leading to targeted delivery of drug combinations in cells for an extended time remains to be elucidated in detail, we found that DcNPs are first taken up into lymph vessels from the subucutaneous space, and subsequently undergo lymphatic first-pass distribution and retention throughout the channels of lymph vessel and node network in the body; this retention of drug in lymph vessels and nodes throughout the body is key to the lymphocyte-targeting and long-acting properties of DcNPs. More detailed discussions of a working hypothesis can be found in these recent papers [61,137,138]. Reviews by our group describe some important results obtained with lipid nanoparticles for drug delivery to lymph nodes and have further discussion on relevant targeting mechanisms [139][140][141].…”

“…Free CAB or RPV released into the extracellular fluid from the intramuscular depot is taken up immediately into the rapidlyflowing blood capillaries, bypassing an opportunity to instead be taken up predominantly by lymphatic capillaries from the intramuscular space, distribute through the lymphatics and accumulate in lymph nodes to produce long-acting PK in both the plasma and lymphocytes. This dissolution and absorption behavior of CAB LA and RPV LA is in contrast to drug combination nanoparticle-associated antiretrovirals in TLC-ART101 that cleared readily form the SC injection site, were predominantly taken into lymph capillaries instead of the blood, distributed through lymph vessels to lymph nodes throughout the body, reached peak plasma levels in non-human primates at ~6 to ~8 hours after injection, and had higher drug levels in lymph node and peripheral blood mononuclear cells than in the plasma [61,137,138]. A recent MRI study of CAB LA in rats confirmed that both intramuscular and SC depots did not readily clear from the injection site and did not distribute to and accumulate in multiple lymph nodes throughout the rat; moreover, consistent with human data, peak plasma drug levels of these drugs after both routes of injection were only achieved after multiple days and had similar shapes in their plasma absorption curves, indicating similar pathways of absorption (from the injection site directly to the blood) but slightly different rates and extents of absorption (likely due to physiological and dissolution rate differences between the two injection sites) [149].…”

“…Once established, the human PK (not only plasma, but also tissue distribution and intracellular drug levels over time) of these formulations must be understood in detail. The formulation-and physiological-related mechanisms that drive the long-acting PK should be elucidated (we recently reported on such mechanisms for TLC-ART101 [137]). Finally, the non-inferiority of long-acting cART approaches versus conventional daily oral cART in nonhuman primate models and humans should be investigated.…”

Perception of People Living With HIV/AIDS Affecting Lost to Follow-Up of ARV Therapy

“…Peneliti berpendapat bahwa hal tersebut dapat terjadi karena adanya fakto -faktor yang lain yang lebih dominan yang menyebabkan responden tidak serius dalam menjalani pengobatan. Jika dilihat dari faktor demografi faktor -faktor tersebut adalah usia responden, lamanya menderita penyakit, serta jarak yang harus ditempuh oleh responden dari rumah untuk mengambil obat ARV (Kraft et al, 2018).…”