HIV

Predicting drug-drug interactions between rifampicin and long-acting cabotegravir and rilpivirine using PBPK modelling

Date: 
12/19/18
Citation: 

Rajoli RKR, Curley P, Chiong J, et al. Predicting drug-drug interactions between rifampicin and long-acting cabotegravir and rilpivirine using PBPK modelling. J Infect Dis. 2019 May 5;219(11):1735-1742. doi: 10.1093/infdis/jiy726. PMID: 30566691; PMCID: PMC6500558.

Cabotegravir and rilpivirine are two long-acting (LA) ARVs that can be administered intramuscularly (IM); their interaction with rifampicin, a first-line anti-TB agent, has not been investigated. The aim of this study was to simulate and predict DDIs between these LA ARV agents and rifampicin using PBPK modelling.

Ultra-long-acting removable drug delivery system for HIV treatment and prevention

Date: 
11/12/18
Citation: 

Kovarova M, Benhabbour SR, Massud I, Spagnuolo RA, Skinner B, Baker CE, Sykes C, Mollan KR, Kashuba ADM, Garcia-Lerma JG, Mumper RJ, Garcia JV. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun. 2018 Oct 8;9(1):4156.  doi: 10.1038/s41467-018-06490-w. PMID: 30297889; PMCID: PMC6175887.

Abstract
Non-adherence to medication is an important health care problem, especially in the treatment of chronic conditions. Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent a viable alternative to improve adherence to HIV/AIDS treatment and prevention. However, the LA-ARV formulations currently in clinical trials cannot be removed after administration even if adverse events occur. Here we show an ultra-LA removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. 

Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention

Date: 
10/1/18
Citation: 

Barrett SE, Teller RS, Forster SP, et al. Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. Antimicrob Agents Chemother. 2018 Sep 24;62(10). PMID: 30012772; PMCID: PMC6153840.

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence.

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

Date: 
8/14/18
Citation: 

Gao Y, Kraft JC, Yu D, Ho RJY.  Recent developments of nanotherapeutics for targeted and long-acting, combination HIV chemotherapy. Eur J Pharm Biopharm. 2019 May;138:75-91. doi: 10.1016/j.ejpb.2018.04.014. Epub 2018 Apr 17. PMID: 29678735; PMCID: PMC6482852.

Combination antiretroviral therapy (cART) given orally has transformed HIV from a terminal illness to a manageable chronic disease. Yet despite the recent development of newer and more potent drugs for cART and suppression of virus in blood to undetectable levels, residual virus remains in tissues.

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

Date: 
2/12/18
Citation: 

Kraft JC, Treuting PM, Ho RJY. 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. 2018 Apr 10;275:229-241. doi: 10.1016/j.jconrel.2018.02.003. Epub 2018 Feb 10. PMID: 29432823; PMCID: PMC5878144.

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.

Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook

Date: 
1/10/18
Citation: 

Mu Q, Yu J, McConnachie LA Kraft JC, Gao Y, Gulati GK, Ho RJY. Translation of combination nanodrugs into nanomedicines: lessons learned and future outlook. J Drug Target. Jun-Jul 2018;26(5-6):435-447. doi: 10.1080/1061186X.2017.1419363. Epub 2018 Jan 10. PMID: 29285948; PMCID: PMC6205718.

For the past two decades, the number of research publications on single-agent nanoformulations has grown exponentially. However, formulations advancing to pre-clinical and clinical evaluations that lead to therapeutic products has been limited.

Health Topics: 

Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities

Date: 
2/12/18
Citation: 

Kraft JC, Treuting PM, Ho RJY. Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities. J Drug Target. 2018 Jun-Jul;26(5-6):494-504. doi: 10.1080/1061186X.2018.1433681. Epub 2018 Feb 12. PMID: 29388438 PMCID: PMC6205717

The distributed network of lymph vessels and nodes in the body, with its complex architecture and physiology, presents a major challenge for whole-body lymphatic-targeted drug delivery. To gather physiological and pathological information of the lymphatics, near-infrared (NIR) fluorescence imaging of NIR fluorophores is used in clinical practice due to its tissue-penetrating optical radiation (700-900 nm) that safely provides real-time high-resolution in vivo images. 

Health Topics: 

Long-acting profile of 4 drugs in 1 anti-HIV nanosuspension in nonhuman primates for 5 weeks after a single subcutaneous injection

Date: 
7/15/18
Citation: 

McConnachie LA, Kinman LM, Koehn J, et al. Long-acting profile of 4 drugs in 1 anti-HIV nanosuspension in nonhuman primates for 5 weeks after a single subcutaneous injection. J Pharm Sci. 2018 Jul;107(7):1787-1790. doi: 10.1016/j.xphs.2018.03.005. Epub 2018 Mar 13. PMID: 29548975; PMCID: PMC6954863.

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. 

Health Topics: 

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