Recent Publications

Translating Cell and Gene Biopharmaceutical Products for Health and Market Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and Future Outlook

Date: 
8/15/20
Citation: 

Bak A, Friis KP, Wu Y, Ho RJY. Translating Cell and Gene Biopharmaceutical Products for Health and Market Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and Future Outlook. J Pharm Sci. 2019 Oct;108(10):3169-3175. doi: 10.1016/j.xphs.2019.05.027. Epub 2019 May 29. PMID: 31150697.

Cell and gene therapies have the potential to be curative for severe disease states such as cancer or incurable orphan genetic diseases. Despite the promise, there are only few such therapies available, although more are appearing in pharmaceutical pipelines. A major culprit limiting a fast translation from preclinical research to the clinic and the market is chemistry, manufacturing and control. The root cause is that most cell and gene therapies currently are personalized in form of ex vivo manipulated cells. This approach stands in sharp contrast to the population-based approach seen for small molecules and protein therapeutics. Therefore, it warrants a different approach to product manufacturing, testing, release, regulatory submissions, and product distribution.

    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

      Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products

      Date: 
      7/27/20
      Citation: 

      Selen A, Müllertz A, Kesisoglou F, Ho RJY, Cook JA, Dickinson PA, Flanagan T. Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products. AAPS J. 2020 Jul 27;22(5):97. doi: 10.1208/s12248-020-00470-z. PMID: 32719954.

      Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377-97, 2014; J Pharm Sci 105:3243-55, 2016).

        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

                  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

                    A Conjoint Analysis of the Acceptability of Targeted Long-Acting Injectable Antiretroviral Therapy Among Persons Living with HIV in the U.S

                    Date: 
                    4/15/20
                    Citation: 

                    Simoni JM, Tapia K, Lee SJ, Graham SM, Beima-Sofie K, Mohamed ZH, Christodoulou J, Ho R, Collier AC. A Conjoint Analysis of the Acceptability of Targeted Long-Acting Injectable Antiretroviral Therapy Among Persons Living with HIV in the U.S. AIDS Behav. 2020 Apr;24(4):1226-1236. doi: 10.1007/s10461-019-02701-7. PMID: 31655915; PMCID: PMC7085450.

                    With long-acting injectable antiretroviral therapy likely to be a treatment option for people living with HIV (PLWH), it is critical to assess its acceptability among potential end-users. Based on formative qualitative work and our own ongoing development of targeted long-acting products in nanosuspension formulations, we created eight hypothetical medication scenarios varying along six dichotomous attributes: administration location (home versus [vs.] clinic), dosing frequency (every 2 weeks vs. 1 week), injections per dose (one vs. two), injection pain (mild vs. moderate), injection site reaction (mild vs. moderate), and effectiveness (better vs. same as pills). PLWH from three outpatient care clinics in Seattle, WA and Riverside, CA rated acceptability (i.e., willingness to try each hypothetical medication) from 0 (very unlikely) to 100 (very likely). In conjoint analyses, we examined level and correlates of acceptability, the impact of each attribute on overall acceptability, and moderators of this effect. 

                    Health Topics: 
                    HIV
                    LA/ER Injectable Therapy

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