Development of sustained release/long acting products for TB

开发结核病缓释/长效产品

• 批准号: 10882260
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 3.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2023-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882260
• 关键词: AIDS prevention; Acute; Adverse event; Animal Model; Animals; Antiviral Agents; Biometry; Bolus Infusion; Cause of Death; Cessation of life; Chronic; Clinical Pathology; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug Kinetics; Event; Excision; Formulation; Frequencies; Goals; HIV; HIV Infections; HIV Seropositivity; HIV/TB; Hepatitis B Virus; Human; Hydrophobicity; Implant; In Situ; In Vitro; Individual; Injectable; Injections; Lung; Macaca; Medicine; Modeling; Mus; Nature; North Carolina; Patients; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Polymers; Population; Preparation; Prevention; Process; Property; Publications; Recommendation; Regimen; Research Personnel; Rifabutin; Rifampin; Rifamycins; Risk; Risk Factors; Safety; Source; Subcutaneous Injections; Technology; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; Tuberculosis; Universities; Work; World Health Organization; allergic response; antiretroviral therapy; biomaterial compatibility; co-infection; compliance behavior; drug action; drug candidate; drug clearance; drug resistance development; improved; isoniazid; liquid formulation; mouse model; multidisciplinary; nonhuman primate; novel; novel therapeutics; pre-exposure prophylaxis; randomized trial; response; subcutaneous; therapeutic effectiveness; translation to humans; transmission process; tuberculosis drugs; tuberculosis treatment

In 2020, 10 million people developed tuberculosis (TB) and 1.5 million people died from TB, marking the first time TB deaths rose in over a decade.1,2 Approximately one-fourth of the world's population has a latent TB infection (LTBI) with the potential for reactivation. These billions of people serve as an ever-present source of new TB cases, independent of ongoing transmission events 3. For people with LTBI, the greatest risk factor for developing TB is HIV co-infection. HIV-infection increases the risk of latent TB reactivation by 20-fold. Further, TB is the leading cause of death of HIV positive individuals. It is thus critical to develop LTBI treatments that are compatible with HIV treatments.4 Short-course, rifamycin-based, 3- or 4-month latent TB infection treatment regimens are preferentially recommended over 6- or 9-month isoniazid monotherapy.5 A single-drug LTBI therapy with a four-month rifampin or rifabutin regimen has been show efective when taken consistently.6- 8 While rifabutin has not been studied in a randomized trial for latent TB treatment, it has reduced potential for drug-drug interactions, which makes it more suitable for treatment of Mtb/HIV coinfections compared to other rifamycins.9-13 Non-adherence to drug regimens has grave consequences and can lead to loss of therapeutic effectiveness and the development of drug resistance.14,15 Long acting (LA) parenteral drug formulations that provide sustained drug release over weeks or months have the potential to reduce dosing frequency such that only one or a few injections of the drug formulation could be sufficient for LTBI treatment. This would dramatically increase treatment compliance and efficacy of treatment16-18. Recently, we developed long-acting formulation of the anti-TB drug rifabutin (RFB) based on In Situ Forming Implant (ISFI) technology (RFB-ISFI). RFB-ISFI is injectable, forms an implant after subcutaneous injection, provides sustained release of RFB for 16 weeks, and is highly effective in mouse models of TB prevention and treatment of acute TB infection (Kim et al 2022). Due to the biocompatible and biodegradable nature of the ISFI polymer, the implant does not need to be removed at the end of treatment. However, if adverse events such as toxicity, drug-drug interactions, or an allergic response occurs, the implant can be safely removed. Drug release properties of ISFI formulations can be manipulated by changes in composition of the liquid formulation and adjusted to meet the specific needs of a given treatment. The scientific premise of this proposal is that the highly effective RFB-ISFI formulation we developed can be used for treatment of LTBI. Our ultimate goal is to develop an injectable formulation, that can be administered once every two months bi-monthly or less frequently and be effective for LTBI treatment, including patients on antiretroviral therapy. To accomplish this goal, we have assembled an outstanding, multi- disciplinary team of investigators with combined demonstrated expertise in animal models, including non-human primates, for studying TB disease and treatment, LA drug delivery systems, pharmacokinetics (PK) analysis, clinical pathology, and biostatistics that will work collaboratively to accomplish the following specific aims.

2020年，有1000万人患结核病，150万人死于结核病，这是有史以来的第一次