Recent Publications - LA/ER Injectable Therapy

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.

Health Topics: 
HIV
LA/ER Injectable Therapy

    Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges

    Date: 
    2/15/18
    Citation: 

    Swindells S, Siccardi M, Barrett SE, et al. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int J Tuberc Lung Dis. 2018 Feb 1; 22(2): 125–132. PMID: 29506608; PMCID: PMC6103451.

    Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. 

    Health Topics: 
    HIV
    LA/ER Injectable Therapy
    Tuberculosis

      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.

      Health Topics: 
      HIV
      LA/ER Injectable Therapy

        Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles

        Date: 
        1/15/18
        Citation: 

        Zhou T, Su H, Dash P, et al. Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials. 2018;151:53-65. doi:10.1016/j.biomaterials.2017.10.023. PMID: 29059541; PMCID: PMC5926202.

        Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people.

        Health Topics: 
        HIV
        LA/ER Injectable Therapy

          Multimodal imaging approach to examine biodistribution kinetics of Cabotegravir (GSK1265744) long acting parenteral formulation in rat

          Date: 
          12/28/17
          Citation: 

          Jucker BM, Alsaid H, Rambo M, et al. Multimodal imaging approach to examine biodistribution kinetics of Cabotegravir (GSK1265744) long acting parenteral formulation in rat. J Control Release. 2017;268:102-112. doi:10.1016/j.jconrel.2017.10.017. PMID: 29042321.

          Long-Acting Parenterals (LAPs) have been used in the clinic to provide sustained therapeutic drug levels at a target site, and thereby reducing the frequency of dosing required. In an effort to understand the factors associated with long-acting cabotegravir (GSK1265744 LAP) pharmacokinetic variability, the current study was designed to investigate the temporal relationship between intramuscular (IM) or subcutaneous (SC) drug depot morphology and distribution kinetics with plasma pharmacokinetics.

          Health Topics: 
          HIV
          LA/ER Implantable Therapy
          LA/ER Injectable Therapy

            Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial

            Date: 
            9/23/17
            Citation: 

            Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499-1510. doi:10.1016/S0140-6736(17)31917-7. PMID: 28750935.

            The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.

            Health Topics: 
            HIV
            LA/ER Injectable Therapy

              In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents

              Date: 
              5/24/17
              Citation: 

              Rajoli RKR, Back DJ, Rannard S, et al. In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents. Clin Pharmacokinet. 2018;57(2):255-266. doi:10.1007/s40262-017-0557-x. PMID: 28540638; PMCID: PMC5701864.

              Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation.

              Health Topics: 
              HIV
              LA/ER Injectable Therapy
              Pediatric Formulations

                Strengths, Weaknesses, Opportunities and Challenges for Long Acting Injectable Therapies: Insights for applications in HIV therapy

                Date: 
                8/1/16
                Citation: 

                Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016;103:144-156. doi:10.1016/j.addr.2016.02.003. PMID: 26916628; PMCID: PMC4935562.

                Many terms have been utilised to describe the LA approach and standardisation would be beneficial.  Ultimately, definitions will depend upon specific indications and routes of delivery.  This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications.

                Health Topics: 
                HIV
                LA/ER Injectable Therapy

                  A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges

                  Date: 
                  3/21/16
                  Citation: 

                  Kovarova M, Swanson MD, Sanchez RI, et al. A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother. 2016 Jun;71(6):1586-96. doi: 10.1093/jac/dkw042. Epub 2016 Mar 21. PMID: 27002074; PMCID: PMC4867102.

                  Objectives:
                  Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission.

                  Health Topics: 
                  HIV
                  LA/ER Injectable Therapy

                    Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV

                    Citation: 

                    Rajoli RK, Back DJ, Rannard S, et al. Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. Clin Pharmacokinet. 2015;54(6):639-650. doi:10.1007/s40262-014-0227-1. PMID: 25523214; PMCID: PMC4450126.

                    These data may help inform the target product profiles for LA antiretroviral reformulation strategies.

                    Health Topics: 
                    HIV
                    LA/ER Injectable Therapy

                      Pages