CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

435 TDF/EVG Nanoparticle Formulation: Plasma Pharmacokinetics in Humanized Mice Christopher Destache ; Subhra Mandal Creighton Univ, Omaha, NE, USA

Background: One of the highest priorities of HIV research is to have access to long-acting pharmaceutical formulations for HIV treatment and prevention. Our research aims at fabrication of combination antiretroviral (cARV) drugs loaded nano-system for PReP. Presently we report on the pharmacokinetics of tenofovir disoproxil fumurate (TDF) and elvitegravir (EVG) loaded nanoparticles (TDF+EVG NP) in humanized mice (huNSG). Methods: Formulation of cARV loaded nanoparticles (NP) by oil-in-water emulsion. Poly(lactic-co-glycolic acid) (PLGA), a biocompatible polymer was used to formulate TDF+EVG drugs loaded NPs (TDF+EVG NPs) using standard methods. For pharmacokinetic studies, female humanized NSG mice (Jackson Labs, Inc.) were treated with TDF+EVG NPs (50 mg/kg administered SubQ in 1 ml D5W). At specific time points (1, 2, 4, 7, 10, and 14 days post-SubQ administration), mice (n=3/time point) were euthanized, blood harvested, centrifuged, and plasma was analyzed for tenofovir (TNF) and EVG drug levels. The plasma concentrations of the drugs were measured by high-performance liquid chromatography (HPLC). Intra-day and inter-day variability was < 10%. Plasma concentration-vs-time was modeled using non-compartmental modeling. Peak plasma levels and time to peak were determined by graph inspection. Results: TDF+EVG NP size averaged 136.7 nm and drug entrapment efficiency was 41.7% and 39.7%, respectively. Mean (+ SD) peak plasma TNF and EVG levels were 1.2 + 0.28 and 0.2 + 0.25 mcg/mL and time to peak was 6.3 and 4.3 days after SubQ administration. Using non-compartmental modeling, plasma PK parameters for TNF and EVG from NP formulation (TDF/EVG NP), respectively, were AUC 0-tau (TNF) 13.5 + 3.1 and EVG 2.2 + 2.9 mg x h/L. Elimination half-life for TNF and EVG averaged 14.9 + 15.1 and 15.2 + 14.9 days, respectively from the NP formulation. Apparent volume of distribution (Vd) averaged 0.027 and 0.497 L/kg and total body clearance (Cl) averaged 0.002 and 0.052 L/day/kg for TNF and EVG, respectively. Based on modeling, a dosing interval of one SubQ dose every 28 days would provide detectable drug in plasma throughout the dosing interval above 50 mcg/mL. Conclusions: The simultaneous administration of TAF and EVG in single NP formulation shows prolonged PK parameters of TNF and EVG. Further tissue concentrations in colon and female reproductive tract are needed to determine if this will be an appropriate prevention option. This is the first report of using NRTI+ISTI in NP formulation for PReP. 436 Antiretroviral Drug Use in a Cross-sectional Population Survey in Africa: HPTN 043 Jessica M. Fogel 1 ;William Clarke 1 ; Michal Kulich 2 ; Estelle Piwowar-Manning 1 ; Glenda Gray 3 ; Linda Richter 4 ; Heidi van Rooyen 5 ;Thomas Coates 6 ; Susan H. Eshleman 1 ; for the HPTN 043 (NIMH Project Accept) StudyTeam 1 Johns Hopkins Univ Sch of Med, Baltimore, MD, USA; 2 Charles Univ, Prague, Czech Republic; 3 South African Med Rsr Council, Cape Town, South Africa; 4 Univ of the Witwatersrand, Johannesburg, South Africa; 5 Human Scis Rsr Council, Durban, South Africa; 6 Univ of California Los Angeles, Los Angeles, CA, USA Background: HIV Prevention Trials Network 043 (NIMH Project Accept) was a community-randomized trial in Africa and Thailand that assessed the impact of behavioral interventions on HIV incidence. Interventions were delivered over 3 years. HIV incidence was then assessed in a cross-sectional survey of >50,000 randomly-sampled adults (survey period: 2009-2011). At the African sites (34 communities at Soweto and KwaZulu-Natal, South Africa; Tanzania; Zimbabwe). HIV incidence was 1.52% and 1.81% in intervention and control communities, respectively (P=0.082). We evaluated antiretroviral drug (ARV) use by HIV-infected adults at these sites. Methods: Plasma samples from 7,352 (99.9%) of the 7,354 HIV-infected adults in the cross-sectional survey were tested for 20 ARV drugs using a qualitative assay (6 nucleoside/ nucleotide reverse transcriptase inhibitors [NRTIs], 3 non-nucleoside reverse transcriptase inhibitors [NNRTIs]; 9 protease inhibitors; maraviroc; raltegravir; lower limit of detection: 10 ng/mL for all drugs). Results: Test results were obtained for 7,347 (99.9%) of the samples. ARVs were detected in 2,011 (27.4%) of the samples (88.1% had 1 NNRTI +/- 1-2 NRTIs; 62.3% had efavirenz; 57.3% had lamivudine). ARV detection was strongly associated with female sex, pregnancy; age (>24 years), and study site (KwaZulu-Natal > Soweto > Tanzania and Zimbabwe), P<0.0001 for all comparisons. ARV detection was also more frequent in widowed compared to married or single adults (P=0.006) and in unemployed compared to employed adults (P=0.02). It was not associated with CD4 cell count, socioeconomic status or education level. ARVs were detected more frequently in the intervention communities compared to the control communities during the first 6 months of the survey (9/2009-3/2010; P=0.02). ARV detection increased over time in intervention communities (from 22.3% in the first 6 months of the survey to 37.7% after 3/2011) and control communities (from 18% in the first 6 months of the survey to 32.4% after 3/2011). Conclusions: The availability of a low-cost, high-throughput multi-drug assay allowed a population-level assessment of ARV use in this large clinical trial. This analysis identified demographic factors associated with ARV use and changes in ARV use over time. Increased ARV use in the control communities, which may have reflected increased HIV testing, referral to care, or access to ARV treatment, could have lowered HIV incidence, which may have impacted the results of this large intervention trial. 437LB A Single Monotherapy Dose of MK-8591, a Novel NRTI, Suppresses HIV for 10 Days Evan Friedman 1 ; Dirk Schuermann 2 ; Deanne J. Rudd 3 ; Sabrina Fox-Bosetti 3 ; Sandra Zhang 3 ; Martine Robberechts 3 ; Andreas Hueser 4 ; Daria J. Hazuda 5 ; Marian Iwamoto 6 ; Jay Grobler 5 ; for the HIV Early DevelopmentTeam 1 Merck & Co, Inc, Rahway, NJ, USA; 2 Charité Rsr Organisation GmbH, Berlin, Germany; 3 Merck & Co., Inc, Kenilworth, NJ, USA; 4 Charité Universitätsmedizin Berlin, Germany, Rsr Hosp, Berlin, Germany; 5 Merck & Co, Inc, West Point, PA, USA; 6 Merck & Co, Inc, Kenilworth, NJ, USA Background: MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in early clinical development. MK-8591-triphosphate (TP), the active phosphorylated anabolite of MK-8591, exhibited protracted intracellular persistence in human and monkey peripheral blood mononuclear cells (PMBCs) in vitro. In preclinical experiments, MK-8591 administered once-weekly in an SIV rhesus macaque model demonstrated potent antiviral efficacy. Clinically, MK-8591-TP exhibited a half-life of ~150-160 hrs in human PBMCs with C 168hr exceeding projected efficacious concentrations at doses of >10 mg. A Phase 1b monotherapy proof-of-concept efficacy study is currently underway to assess the potential for once weekly oral dosing in the clinic. The antiviral potency, human pharmacokinetics (PK), and physical properties of MK-8591 have the potential to open new paradigms for extended duration HIV treatment and prophylaxis approaches. Methods: In an open label study in HIV-1 infected subjects naïve to antiretroviral treatment (ART), subjects are being administered a single dose of MK-8591 across a range of doses. Doses were chosen based on PK/PD simulations. Blood samples are being collected for viral load (VL), MK-8591 PK, and MK-8591-TP PK at prespecified time points up to 10 days postdose. Following completion of Day 10 procedures, subjects are being offered standard of care ART. Safety, PK, and VL data from the 10-mg dose (N=6) are available. Results: A single 10 mg dose of MK-8591 was associated with a rapid and robust reduction in VL. At 168 hours postdose, a mean (95% CI) placebo adjusted VL reduction of 1.67 log10 (1.47, 1.87) was observed. Mean VL continued to decline through Day 10 with a mean reduction of 1.78 log10 (1.59, -1.98) and no evidence of recrudescence. The 10-mg dose was generally well tolerated with a limited number of mild/moderate adverse experiences reported. MK-8591 plasma and MK-8591-TP PBMC PK were similar to previously reported data in healthy subjects. Conclusions: MK-8591 suppressed HIV replication for at least ten days when administered as a single 10 mg dose. The low dose and potent antiviral effect of MK8591 provides a platform for extended duration oral and parenteral formulations.

Poster Abstracts

166

CROI 2016