Share
Title
Transformation of 3 current short-acting HIV drugs, tenofovir, lamivudine and dolutegravir (TLD) into a novel, all-in-one long-acting TLD 3-drug-combination in a single injectable dosage that produces extended pharmacokinetics
Presenter
Rodney JY Ho
Authors
R.J. Ho1, Z.R. Stephen2, S. Perazzolo2, J. Lo2, X. Xu2, Y. Zhao2, M. Eguchi2, M. Hartman2, C. Jonsson3, A.J. Melvin4, A.C. Collier5
Institutions
1University of Washingtron, Pharmaceutics and Bioengineering, Seattle, United States, 2University of Washington, Pharmaceutics, Seattle, United States, 3University of Washington, Pharmaceutics and Medicine, Seattle, United States, 4University of Washington, Pediatrics, Seattle, United States, 5University of Washington, Medicine, Seattle, United States

BACKGROUND: Introduction of long-acting Cabenuva, containing two HIV drugs, cabotegravir and rilpivirine, in two-intramuscular injections for HIV treatment is a significant step toward addressing adherence and pill fatigue. However, clinical and programmatic issues limit Cabenuva uptake worldwide. WHO has an on-going initiative to distribute a short-acting oral product called TLD (tenofovir, lamivudine & dolutegravir). Advantages to dolutegravir in TLD include its higher barrier to resistance than cabotegravir, but oral TLD requires daily dosing. Thus, the goal of this study is to develop a Next-Gen long-acting TLD 3-drug combination treatment in a single subcutaneous injection.
METHODS: Previously, we reported on biocompatible lipid-excipients and a process to stabilize multiple HIV drugs with disparate physical-chemical (including water solubility) properties. This technology enables transformation of current HIV drugs (including water-insoluble lopinavir, ritonavir, efavirenz, atazanavir and water soluble tenofovir, lamivudine) into drug-combination nano-particulate (DcNP) products that are stable in suspension. Employing the DcNP process, lipid excipients composed of distearoyl-phosphatidyl-choline (DSPC) and distearoyl-phosphatidyl-ethanolamine derivatized with polyethylene-glycol (MW=2000) or mPEG2000-DSPE were systematically tested to produce a stable, sterile TLD suspension for non-human-primate (NHP) studies. M. nemestrina (~5-8 kg, n=8) were given a single subcutaneous injection of TLD in DcNP (6.2/5/10 mg/kg) and a plasma time-course was determined.
RESULTS: TLD-DcNP product was prepared by (1) dissolving TLD with lipid-excipients in hydrated-alcohol, followed by controlled solvent-removal process to produce TLD-DcNP powder; (2) the particle-size of TLD-DcNP in saline suspension was reduced (d~60-80 nm) resulting in a stable- injectable TLD product, suitable for subcutaneous dosing.
Compared to the free-and-soluble form for which TLD concentrations fell below detectable levels within a few hours as previously reported, the DcNP formulation demonstrated a long-acting plasma time-course for all 3-drugs when given as a single subcutaneous dose. While NHP plasma TLD levels for DcNP dosage-forms were different for each drug substance, at the dose tested, all 3 drugs sustained concentrations above EC50 > 4 weeks. These data were reproducible in making TLD-DcNP product and in NHP pharmacokinetic profile.
CONCLUSIONS: We have successfully developed a process that transforms short-acting to long-acting TLD into an all-in-one subcutaneous injection product for consideration of clinical development.
Supported by UNITAID GLAD and NIH

Download the e-Poster (PDF)

Download the e-Poster (Movie)