EACS2023: 192 Targeting emtricitabine to HIV reservoir in mesenteric lymph nodes using lipophilic prodrug approach and lipidic formulation G. Sinatra , L. Ji , Y. Chu , A. Wong , M. Ashford , J. Butler , S. Stolnik , M.J. Stocks , P. Gershkovich University of Nottingham, School of Pharmacy, Nottingham, United Kingdom, AstraZeneca, Pharmaceutical Sciences R&D, Cambridge, United Kingdom, GlaxoSmithKline, R&D, Ware, United Kingdom General data Abstract category: Antiretroviral drugs preclinical Abstract body Purpose: This work aims to improve emtricitabine (FTC) delivery to HIV reservoirs within the intestinal lymphatics through chylomicrons association, by synthesising lipophilic prodrug derivatives for oral administration. Ideal prodrugs should exhibit high chylomicrons association, high stability in the gastrointestinal tract, efficient release of the active drugs in lymph/plasma, and high triglyceride solubility. Method: To enable FTC's association with chylomicrons, lipophilic prodrug derivatives designed using a computational model (Gershkovich, P., et al. , 2009) were synthesised. The prodrugs were assessed in vitro for stability in simulated intestinal fluids (FaSSIF) and plasma (as a lymph surrogate), and for affinity to artificial chylomicrons emulsion (Lee, J.B., et al. , 2018; Qin, C., et al. , 2021). Prodrugs triglyceride solubility was also assessed. Results: FTC in silico and in vitro chylomicrons association and its solubility in sesame oil (Table 1) were negligible, suggesting minimal intestinal lymphatic transport. In contrast, all prodrugs exhibited higher chylomicrons association compared to FTC, consistent with computational predictions (Figure 1A). More sterically hindered prodrugs showed prolonged stability in plasma and FaSSIF ( Figure 1B). The introduction of double bonds in the promoiety led to significant reduction of half-life in both plasma and FaSSIF, but it also increased the triglyceride solubility (Table 1). Fig. 1. A) In silico and in vitro (Intralipid®, 100 mg/dL TG concentration) chylomicrons association. B) In vitro prodrugs’ stability in rat plasma and FaSSIF with added esterase activity (20 IU/mL). Table 1. FTC and prodrugs solubility in sesame oil (Mean ± SD). Compound Solubility in sesame oil (mg/mL) FTC 0.02 ± 0.001 EC16 0.36 ± 0.020 EOA 36.5 ± 10.300 Conclusions: All prodrugs showed higher chylomicrons association than FTC. Prodrugs with unsaturated promoieties showed high triglyceride solubility, but limited stability in environment mimicking gastrointestinal tract. In contrast, prodrugs containing saturated promoieties were more stable in gastrointestinal tract environment. Future work will focus on increasing the triglyceride solubility. If successful, these prodrugs could improve FTC delivery to the HIV reservoir within the intestinal lymphatics. General conditions 1. I confirm that I previewed this abstract and that all information is correct. I accept that the content of this abstract cannot be modified or corrected after the submission deadline and I am aware that it will be published exactly as submitted.: Yes 2. I confirm that the submission of the abstract constitutes my consent to publication (e.g. conference website, programmes, other promotions, etc.). : Yes 3. I herewith confirm that the contact details saved in this system are those of the corresponding author, who will be notified about the status of the abstract. The corresponding author is responsible for informing the other authors about the status of the abstract.: Yes 4. I agree that all data provided may be used (saved, stored, processed, transmitted and deleted) in compliance with the privacy policy to provide the services described.: Yes 1 1 1 1 2 3 1 1 1 1 2 3 76 19TH EUROPEAN AIDS CONFERENCE | WARSAW 2023
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