The increasing global prevalence of human immunodeficiency virus (HIV) is estimated at 36.7 million people currently infected. Lifelong antiretroviral (ARV) drug combination dosing allows management as a chronic condition by suppressing circulating viral load to allow for a near-normal life; however, the daily burden of oral administration may lead to non-adherence and drug resistance development. Long-acting (LA) depot injections of nanomilled poorly water-soluble ARVs have shown highly promising clinical results with drug exposure largely maintained over months after a single injection. ARV oral combinations rely on water-soluble backbone drugs which are not compatible with nanomilling. Here, we evaluate a unique prodrug/nanoparticle formation strategy to facilitate semi-solid prodrug nanoparticles (SSPNs) of the highly water-soluble nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC), and injectable aqueous nanodispersions; in vitro to in vivo extrapolation (IVIVE) modelling predicts sustained prodrug release, with activation in relevant biological environments, representing a first step towards complete injectable LA regimens containing NRTIs.

1-Deoxy-d-xylulose 5-phosphate (DXP) synthase is the first enzyme in the methylerythritol phosphate pathway to essential isoprenoids in pathogenic bacteria and apicomplexan parasites. In bacterial pathogens, DXP lies at a metabolic branchpoint, serving also as a precursor in the biosynthesis of vitamins B1 and B6 which are critical for central metabolism. Toward identifying novel bisubstrate analog inhibitors that exploit the large active site and distinct mechanism of DXP synthase, a library of aryl mixed oximes was prepared and evaluated. Trihydroxybenzaldoximes emerged as reversible, low micromolar inhibitors, competitive against d-glyceraldehyde 3-phosphate (d-GAP) and either uncompetitive or noncompetitive against pyruvate. Hydroxybenzaldoximes are the first class of d-GAP-competitive DXP synthase inhibitors offering new tools for mechanistic studies of DXP synthase and a new direction for the development of antimicrobial agents targeting isoprenoid biosynthesis.

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A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration-approved manufacturer's labels, and published studies in the literature. One hundred twenty-six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty-two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information.

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The facile formation of drug nanoparticles in injectable/ingestible oils, of water-soluble antiretroviral tenofovir disoproxil fumarate, using a novel nanoprecipitation is presented with studies showing drug release into relevant aqueous media.

Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah−/− humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models.

Most current antiretroviral (ARV) medications for HIV treatment and prevention necessitate lifelong daily dosing, and require high levels of patient adherence to be effective. Long‐acting injectable (LAI) ARVs would allow less frequent administration, improving adherence. Technologies currently used to produce LAI‐ARVs are incompatible with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) due to their high water solubility. It is critical to overcome this challenge to development of LAI NRTI strategies as most current ARV combination therapies include NRTI backbone therapies. We synthesized a series of carbamate‐based emtricitabine (FTC) prodrugs to increase hydrophobicity and improve compatibility for solid drug nanoparticle (SDN) formation. Prodrug activation kinetics were assessed in vitro via HPLC in human muscle, plasma, and liver fractions. Prodrugs were then screened for SDN compatibility using an emulsion templated/freeze drying method. Hits from these screens are defined by the following properties: Z‐average diameter <1000 nm, a polydispersity index of <0.5, and the ability to disperse in water at a concentration of 1 mg/mL. Prodrug release from SDNs and subsequent enzymatic conversion to FTC was quantified by HPLC in human muscle fractions in vitro. Carbamates bearing longer alkyl chains (C7 and C8) were most efficiently activated in all conditions. Hydrolysis rates in liver were higher than those in plasma or muscle.Carbonate moieties at the 5′‐position were hydrolyzed more efficiently than the carbamate moiety under all conditions. Nanoparticle screening at 10 wt% prodrug demonstrated a correlation between calculated logP and the number of hits obtained for carbamate/carbonate prodrugs (39/42), but not for carbamate‐only prodrugs (4/42). Formation of nanoparticles with higher drug loadings was also demonstrated with a hit for an octyl carbamate/carbonate FTC prodrug SDN achieved at 70 wt%. Assessments of in vitro prodrug release from SDNs monitoring FTC formation over time suggested that prodrug release is rate‐limiting under conditions of high SDN concentration. Taken together, this work suggests that carbamate‐based prodrug approaches offer a promising starting point for development of LAI FTC toward a complete LAI‐ARV regimen to improve adherence.Support or Funding InformationNIH 1F31AI129549NIH 5R01AI114405This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.