Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation.
J Control Release
; 275: 229-241, 2018 04 10.
Article
en En
| MEDLINE
| ID: mdl-29432823
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 1â¯week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2â¯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.
Palabras clave
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (PubChem CID: 94190); 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) (DSPE-mPEG(2000)) (PubChem CID: 406952); Antiretrovirals; HIV drug combination treatment; Long-acting; Lopinavir (PubChem CID: 92727); Lymphatic drug insufficiency; Lymphatic targeted drug delivery; Mechanism-based pharmacokinetic modeling; Ritonavir (PubChem CID: 392622); Tenofovir (PubChem CID: 464205)
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ritonavir
/
Fármacos Anti-VIH
/
Antirretrovirales
/
Nanopartículas
/
Lopinavir
/
Tenofovir
/
Modelos Biológicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Control Release
Asunto de la revista:
FARMACOLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos