CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Results: TAF release in-vitro from the active devices followed a zero-order release kinetics (1.1±0.02 mg/d) during study period. Similarly, plasma concentrations indicated the implanted devices maintained a low systemic exposure of TAF with a median concentration of 0.4±0.1 ng/mL. Low systemic exposure to TFV was also demonstrated attaining a median concentration of 9.4±2.6 ng/mL. PBMC loading with TFV-DP was noted at the first sampling time point and was maintained throughout the study period at a median level of 1825±820 fmol/10 6 cells (or 9125 nM) (Figure 1). Residual drug analysis of the retrieved devices approximated the in-vivo release rate of TAF to be 1.1±0.01 mg/d. Of note, some animals exhibited cutaneous responses (i.e., encapsulation and swelling) to the active devices. Conclusion: The sustained plasma TAF concentrations and the in-vivo release rate of the active implants correlated well with the in-vitro TAF release from similar devices. TAF implants maintained sustained PBMC TFV-DP concentrations for the duration of the 49d mid-point evaluation well above that predicted for HIV PrEP in humans. Taken together, these data indicate this TAF device is suitable for continued development as a long-acting subcutaneous implant for HIV PrEP.

exhibit higher levels, especially for EFV and LPV, than those found in plasma. All three drugs also exhibit lymph node drug concentrations higher than plasma (table 1). Conclusion: Collectively, this 3-in-1 DcNP formulation provided long-acting plasma drug concentration and enhanced HIV host-cell localization in cells in blood and also lymph nodes. This anti-HIV DcNP formulation should be considered for development intended for pediatrics. With long-acting profile and higher penetration/persistence in cells, it may enhance therapeutic efficacy of these well-studied HIV drugs due to co-localization of a combination of three drugs.

Poster Abstracts

488 LONG-ACTING PHARMACOKINETICS OF 4 HIV DRUGS COFORMULATED IN ONE NANO-FORMULATION Lisa McConnachie , Loren Kinman, Josefin Koehn, John C. Kraft, Sarah Lane,

Wonsok Lee, Ann Collier, Rodney J. Ho University of Washington, Seattle, WA, USA

Background: Daily oral conventional ART, even in fixed dose combination forms, has inherent limitations such as patient adherence and disparate drug kinetics; both potentially impacting therapeutic outcomes. Oral dosing has also been shown to produce lower and limited tissue exposure where residual virus persists. To address these limitations, we have developed a tissue- and cell-targeted long-acting anti-HIV nanosuspension containing 4 drugs. The aim of this study is to characterize the blood and tissue pharmacokinetics of all four drugs 5 weeks following drug administration. Methods: Four pigtail macaques received a single subcutaneous injection of a 4-in-1 anti-HIV drug combination nanoparticle (DcNP) formulation composed of lopinavir (LPV), ritonavir (RTV), tenofovir (TFV) lamivudine (3TC) and lipidic excipients. Blood samples and lymph node biopsies were obtained at defined time points up to 5 weeks following drug administration. Drug levels in plasma, lymph node and peripheral blood mononuclear cells (LNMC and PBMC) were analyzed with a validated LC-MS/MS assay. Results: The injections were well tolerated and no injection site reactions were noted. PBMC and plasma levels of the three active drugs (hydrophobic LPV, hydrophilic TFV and 3TC) were sustained for 5 weeks; these data are depicted in Figure 1. When compared to plasma levels, PBMC drug exposures were 12-, 16-, and 42-fold higher for LPV, RTV, and 3TC, respectively. Notable extended apparent terminal half-lives of LPV, TFV, and 3TC were observed in plasma [219.1 hours (LPV), 63.1 hours (TFV), and 136.3 hours (3TC)]. These were even further extended in PBMCs [1045.7 hours (LPV), 105.9 hours (TFV), and 127.7 hours (3TC)]. Eight days after drug administration, LPV, TFV and 3TC levels in LNMCs were 102-, 2.9-, and 352-fold higher than those in plasma. Conclusion: A single injection of one DcNP nanosuspension containing four drugs exhibited persistent drug levels in LMNC, PBMC, and plasma for 5 weeks. Though these drugs have disparate physiochemical properties, we were able to successfully co-formulate all into a single nanosuspension. This formulation demonstrated both cell- and tissue-targeted properties in addition to sustained pharmacokinetic profiles. With interspecies scaling and appropriate dose adjustments, this 4-in-1 HIV drug-combination could be considered for long- acting treatment with the potential to overcome lymphatic drug insufficiency and limitations with patient adherence.

487 LONG-ACTING 3 HIV-DRUGS-IN-ONE NANOPARTICLE FORMULATION INTENDED FOR ADOLESCENTS Josefin Koehn , John C. Kraft, Lisa McConnachie, Loren Kinman, Sarah Lane,

Wonsok Lee, Ann Collier, Rodney J. Ho University of Washington, Seattle, WA, USA

Background: It is estimated that about 2.1 million children worldwide are living with HIV. Due to their physio-pharmacological distinction, pediatric drug treatments require age appropriate dosage form. However, the development of therapeutics aimed at suppressing HIV in children and adolescents has been limited. In contrast to a larger selection of oral combination antiretroviral therapies (cART) available for adults, the options for children are somewhat limited. Also, data indicates that only about 30% of adolescents experience durable viral suppression. Even in cases with plasma viral suppression, residual virus can be isolated from tissues, particularly lymph nodes. Therefore, we have developed a drug combination nanoparticle (DcNP) containing three drugs with well-established antiviral potency and safety in pediatrics, targeting three different stages in the viral replication. This DcNP is composed of a protease inhibitor lopinavir (LPV), nonnucleoside reverse transcriptase inhibitor efavirenz (EFZ), and nucleoside inhibitor tenofovir (TFV). The objective of this study was to characterize targeted and long-acting effects of our validated 3-drug single DcNP formulation in HIV host cells and plasma in non-human primates for two weeks. Methods: Macaques were given a single dose of the DcNP subcutaneously. The drug concentrations in plasma, peripheral blood, and lymph mononuclear cells were analyzed for two weeks. The pharmacokinetic parameters and cell-to- plasma relationship of the three drugs were determined. Results: The formulation was well-tolerated in primate and no local reactions were noted. We found that protease inhibitor (LPV) and reverse transcriptase inhibitor (EFV, TFV) levels persist in plasma for the two week duration of the study. Intracellular levels for all three drugs also persist for two weeks and

CROI 2018 175