Recent Publications

Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

Date: 
9/12/21
Citation: 

Neyens M, Crauwels HM, Perez-Ruixo JJ, Rossenu S. Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV. J Antimicrob Chemother. 2021 Sep 12:dkab338. doi: 10.1093/jac/dkab338. Epub ahead of print. PMID: 34510179.

Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks).

Health Topics: 
HIV

    "Lighten This Burden of Ours": Acceptability and Preferences Regarding Injectable Antiretroviral Treatment Among Adults and Youth Living With HIV in Coastal Kenya

    Date: 
    6/29/21
    Citation: 

    Simoni JM, Beima-Sofie K, Wanje G, Mohamed ZH, Tapia K, McClelland RS, Ho RJY, Collier AC, Graham SM. "Lighten This Burden of Ours": Acceptability and Preferences Regarding Injectable Antiretroviral Treatment Among Adults and Youth Living With HIV in Coastal Kenya. J Int Assoc Provid AIDS Care. 2021 Jan-Dec;20:23259582211000517. doi: 10.1177/23259582211000517. PMID: 33685272; PMCID: PMC7952847.

    Since 2010, the global scale-up of antiretroviral therapy (ART) has contributed to a 50% decline in global annual deaths from AIDS-related illness, from a peak of 1.9 million in 2005 to 940,000 in 2017, highlighting the importance of ART in reducing morbidity and mortality.1 However, UNAIDS has estimated that only 77% of diagnosed persons living with HIV are accessing ART, and only 82% of patients on ART have suppressed viral loads,2 suggesting there is room for improvement in adherence.

    Health Topics: 
    HIV
    LA/ER Injectable Therapy

      The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

      Date: 
      6/29/21
      Citation: 

      Scarsi KK, Swindells S. The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data? J Int Assoc Provid AIDS Care. 2021 Jan-Dec;20:23259582211009011. doi: 10.1177/23259582211009011. PMID: 33902356; PMCID: PMC8082990.

      As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products.

      Health Topics: 
      HIV

        Identification of a novel long-acting 4’-modified nucleoside reverse transcriptase inhibitor against HBV

        Date: 
        3/19/21
        Citation: 

        Higashi-Kuwata N, Hayashi S, Kumamoto H, Ogata-Aoki H, Das D, Venzon D, Hattori SI, Bulut H, Hashimoto M, Otagiri M, Takamune N, Kishimoto N, Davis D, Misumi S, Kakuni M, Tanaka Y, Mitsuya H. Identification of a novel long-acting 4'-modified nucleoside reverse transcriptase inhibitor against HBV. J Hepatol. 2020 Dec 14:S0168-8278(20)33843-5. doi: 10.1016/j.jhep.2020.12.006. Epub ahead of print. PMID: 33333207.

        Although there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve out-comes and quality of life. Herein, this study reports preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible,which is preferable to the current daily dosing regimens.

        Health Topics: 
        LA/ER Oral Therapy
        Viral Hepatitis

          Predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis across three phase 3 studies

          Date: 
          3/18/21
          Citation: 

          Cutrell AG, Schapiro JM, Perno CF, Kuritzkes DR, Quercia R, Patel P, Polli JW, Dorey D, Wang Y, Wu S, van Eygen V, Crauwels H, Ford SL, Baker M, Talarico CL, Clair MST, Jeffrey J, White CT, Vanveggel S, Vandermeulen K, Margolis DA, Aboud M, Spreen WR, van Lunzen J. Predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis across three phase 3 studies. AIDS. 2021 Mar 16. doi: 10.1097/QAD.0000000000002883. Epub ahead of print. PMID: 33730748.

          Efficacy and safety of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc.

          Health Topics: 
          HIV
          LA/ER Oral Therapy

            Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study

            Date: 
            12/9/20
            Citation: 

            Overton ET, Richmond G, Rizzardini G, Jaeger H, Orrell C, Nagimova F, Bredeek F, Deltoro MG, Swindells S, Andrade-Villanueva JF, Wong A, Khuong-Josses M, Solingen-Ristea RV, Eygen VV, Crauwels H, Ford S, Talarico C, Benn P, Wang Y, Hudson KJ, Chounta V, Cutrell A, Patel P, Shaefer M, Margolis DA, Smith KY, Vanveggel S, Spreen W. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study, The Lancet, 2020, ISSN 0140-6736.

            Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. 

            Health Topics: 
            HIV
            LA/ER Oral Therapy

              Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV

              Date: 
              11/6/20
              Citation: 

              Flexner C, Owen A, Siccardi M, Swindells S. Long-Acting Drugs and Formulations for the Treatment and Prevention of HIV, International Journal of Antimicrobial Agents, 2020, 106220,ISSN 0924-8579.

              Long acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early and late stage clinical trials. Strategies to manage toxicities and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations.

              Health Topics: 
              HIV

                Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP)

                Date: 
                11/5/20
                Citation: 

                Li L, Johnson LM, Krovi SA, Demkovich ZR, van der Straten A. Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP). Pharmaceutics. 2020; 12(11):1057.

                A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAFFB) in this long-acting implant platform, as TAFFB maintains higher chemical stability than the TAF hemifumarate salt (TAFHF). 

                  Application of Clinical Pharmacology Principles in Drug Development of Modified-Release Products: Leveraging Exposure-Response Information to Support Approval

                  Date: 
                  11/3/20
                  Citation: 

                  AbuAsal BS, Hamed SS, Ahmed MA, Al-Mansour L, Uppoor R, Mehta M. Application of Clinical Pharmacology Principles in Drug Development of Modified-Release Products: Leveraging Exposure-Response Information to Support Approval. J Clin Pharmacol. 2020 Nov;60(11):1441-1452. doi: 10.1002/jcph.1637. Epub 2020 May 26. PMID: 32453882.

                  The development of modified-release (MR) drug products aims to address a clinical need such as improving patient compliance. There are multiple pathways and development strategies for the registration and approval of MR products. The development strategy of an MR product is usually dependent on the availability and pharmacokinetic/pharmacodynamics (PK/PD) characteristics of the reference drug product, that is, an immediate-release (IR) product or a reference MR. Compared with a reference IR product, an MR product is likely to have a different PK profile over the least common dosing time due to unequal dosing intervals. In case of differences in PK profiles between the MR product and the reference product, confirmatory efficacy and safety studies may be needed to support registration. 

                    Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules

                    Date: 
                    9/23/20
                    Citation: 

                    Yu J, Mu Q, Perazzolo S, Griffin JI, Zhu L, McConnachie LA, Shen DD, Ho RJ. Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules. Pharm Res. 2020 Sep 23;37(10):197. doi: 10.1007/s11095-020-02888-8. PMID: 32968837.

                     GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed. A GT distribution study into cancer nodules (derived from 4 T1 cells) was performed.

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