HIV

A year-long extended release nanoformulated cabotegravir prodrug

Date: 
8/15/20
Citation: 

Kulkarni TA, Bade AN, Sillman B, et al. A year-long extended release nanoformulated cabotegravir prodrug. Nat Mater. 2020;19(8):910-920. doi:10.1038/s41563-020-0674-z

Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution.

Health Topics: 
HIV
LA/ER Injectable Therapy
Tuberculosis

    Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir

    Date: 
    8/10/20
    Citation: 

    Yu J, Yu D, Lane S, McConnachie L, Ho RJY. Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir. J Pharm Sci. 2020 Aug 10:S0022-3549(20)30434-2. doi: 10.1016/j.xphs.2020.08.003. Epub ahead of print. PMID: 32791073.

    Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugs-water-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = -1.6). 

    Health Topics: 
    HIV

      LEAP Extended for 5 Years

      Date: 
      7/28/20

      Long-Acting/Extended Release Antiretroviral Research Resource Program to add therapy development for tuberculosis and viral hepatitis

      July 28, 2020—The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) today announced approval of a new NIH grant that allows for expansion of its charter to promote development of medications that are more manageable for patients. Going forward LEAP will include tuberculosis and viral hepatitis, which are comorbidities that complicate HIV treatment.

        Pharmacokinetics, Safety and Tolerability of Long-Acting Parenteral Intramuscular Injection Formulations of Doravirine

        Date: 
        6/5/20
        Citation: 

        Yee KL, Mittal S, Fan L, et al. Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine [published online ahead of print, 2020 Jun 5]. J Clin Pharm Ther. 2020;10.1111/jcpt.13182. doi:10.1111/jcpt.13182. PMID: 32501541.

        Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection.

        Health Topics: 
        HIV
        LA/ER Injectable Therapy

          The Potential Impact of Long-Acting Cabotegravir for HIV Prevention in South Africa: A Mathematical Modelling Study

          Date: 
          6/3/20
          Citation: 

          Smith JA, Garnett GP, Hallett TB. The Potential Impact of Long-Acting Cabotegravir for HIV Prevention in South Africa: A Mathematical Modelling Study. J Infect Dis. 2020 Jun 3. pii: jiaa296. doi: 10.1093/infdis/jiaa296. [Epub ahead of print] PMID: 32492704.

          Although effective, some oral pre-exposure prophylaxis (PrEP) users face barriers to adherence using daily pills, which could be reduced by long-acting formulations. Long-acting cabotegravir (CAB LA) is a potential new injectable formulation for HIV PrEP being tested in Phase III trials.

          Health Topics: 
          HIV
          LA/ER Injectable Therapy
          Pre-exposure Prophylaxis (PrEP)

            Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine

            Date: 
            6/2/20
            Citation: 

            Verma M, Chu JN, Salama JAF, et al. Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine. Proc Natl Acad Sci U S A. 2020;117(22):11987-11994. doi:10.1073/pnas.2004746117

            Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. 

            Health Topics: 
            HIV
            Tuberculosis
            Viral Hepatitis

              Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV

              Date: 
              6/1/20
              Citation: 

              Bollinger RC, Thio CL, Sulkowski MS, McKenzie-White J, Thomas DL, Flexner C. Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV. Lancet HIV. 2020 Jun;7(6):e443-e448. doi: 10.1016/S2352-3018(19)30342-X. Epub 2019 Dec 20. PMID: 31870675; PMCID: PMC7376366.

              The first long-acting formulations of HIV drugs are undergoing regulatory review for use in maintenance of viral suppression in people with HIV. Although these novel drug formulations could contribute greatly to HIV treatment and prevention efforts, their lack of activity against hepatitis B virus (HBV) could limit their global impact, particularly in populations with high burdens of both HIV and HBV.

              Health Topics: 
              HIV
              LA/ER Injectable Therapy
              Viral Hepatitis

                Predicting pharmacokinetics of a tenofovir alafenamide subcutaneous implant using PBPK modelling

                Date: 
                5/18/20
                Citation: 

                Rajoli RKR, Demkovich ZR, Flexner C, Owen A, Siccardi M. Predicting pharmacokinetics of a tenofovir alafenamide subcutaneous implant using PBPK modelling. Antimicrob Agents Chemother. 2020 May 18:AAC.00155-20. doi: 10.1128/AAC.00155-20. PMID: 32423957.

                Long-acting (LA) administration using a subcutaneous (SC) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological (PK) profile and overcome sub-optimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV pre-exposure prophylaxis (PrEP). Daily drug-release requirements were then ascertained by averaging across the dosing interval.

                Health Topics: 
                HIV
                LA/ER Implantable Therapy

                  Long-acting injectable cabotegravir is highly effective for the prevention of HIV infection in cisgender men and transgender women who have sex with men

                  Date: 
                  5/18/20

                  The HIV Prevention Trials Network (HPTN) announced today results from HPTN 083, a global randomized, controlled, double-blind study that compared the safety and efficacy of long-acting injectable cabotegravir (CAB LA) to daily oral tenofovir/emtricitabine (TDF/FTC) (Truvada) for pre-exposure prophylaxis (PrEP). The study showed that CAB LA lowered HIV incidence among cisgender men and transgender women who have sex with men. During a planned review of study data, an independent Data and Safety Monitoring Board (DSMB) recommended that the study results be announced as soon as possible. The study sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, agreed with this recommendation.

                  Health Topics: 
                  HIV
                  LA/ER Injectable Therapy

                    Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101

                    Date: 
                    5/15/20
                    Citation: 

                    Perazzolo S, Shireman LM, McConnachie LA, Koehn J, Kinman L, Lee W, Lane S, Collier AC, Shen DD, Ho RJY. Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101. J Pharm Sci. 2020 May;109(5):1789-1801. doi: 10.1016/j.xphs.2020.01.016. Epub 2020 Jan 29. PMID: 32006525.

                    TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive. Therefore, an intravenous study of TLC-ART 101 in nonhuman primates was conducted to elucidate the degree of association of drugs in vivo, estimate subcutaneous bioavailability, and refine a mechanism-based pharmacokinetic (MBPK2) model. The MBPK2 model considers TLC-ART 101 systemic drug clearances, nanoparticle-associated/dissociated species, more detailed mechanisms of lymphatic first-pass retention of associated-drugs after subcutaneous administrations, and the prediction of drug concentration time-courses in lymph node mononuclear cells. 

                    Health Topics: 
                    HIV

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