Graduation Date

Summer 8-9-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Benson J. Edagwa

Second Advisor

Dr. Howard E. Gendelman

Abstract

Dolutegravir (DTG) is an integrase strand transfer inhibitor (INSTI) widely used as a part of first-line combination antiretroviral therapy. DTG has a high barrier to resistance However, one therapeutic challenge centers on its life-long daily use. Sub-optimal adherence to daily oral pills underscore the need for long-acting formulations. To these ends, our research activities have focused on the development and translation of ultra-long-acting ART. Monomeric ester prodrugs provided initial success in extending the apparent half-life of DTG and other INSTIs. One is the DTG prodrug formulation called NM2DTG. NM2DTG’s significantly extended the parent drug’s apparent half-life [Nature Communications, 3226 (2022)]. To reduce injection volumes, address the pharmacokinetic tail limitation, facilitate drug formulation depots, and sustain DTG plasma concentrations novel chemical drug modifications were created. The intent to achieve each of these goals without drug dose adjustments led to the creation of a library of DTG homodimer prodrugs. These were synthesized by covalently linking two parent drug molecules to an 18, 20, or 22-carbon fatty diacid to form M4-, M7-, and M8-DTG, respectively. A control ionizable DTG prodrug monomer (M6DTG) was made by esterifying one of the two carboxylate groups in the optimal 18-carbon fatty diacid. Chemical characterization confirmed the DTG derivatization. The dimeric prodrug nanoformulations were retained within human monocyte-derived macrophages (MDM) over a 30 day experiment period. Pharmacokinetic screening of the prodrugs after single intramuscular (IM) injections of BALB c/J mice identified NM4DTG as the lead candidate. A single IM injection of NM4DTG at 50 mg DTG-eq./kg IM into mice demonstrated controlled release of sustained DTG levels above 4x PA-IC90 for 4 months followed by a rapid drug decay, demonstrating a short PK tail. By comparison, native DTG formulation (NDTG), NM7DTG and NM8DTG exhibited suboptimal PK profiles. The NM4DTG PK data sets were replicated in Sprague Dawley rats administered single intramuscular (IM) or subcutaneous (SC) injections. Both SC and IM injections of NM4DTG in rats were well tolerated. The unique physicochemical properties of NM4DTG and high DTG loading per prodrug unit mass contribute to the short PK tail and sustained high plasma DTG exposure. Altogether, these data sets support further development of NM4DTG as a low injection volume 3-month injectable formulation for treatment and prevention of HIV-1 infection.

Comments

2024 Copyright, the authors

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