Pharmacokinetic and pharmacodynamic evaluation of HIV-1 pre-exposure prophylaxis candidates in humanized mice
Date
2014
Authors
Veselinovic, Milena, author
Akkina, Ramesh, advisor
Aboellail, Tawfik, committee member
Gonzalez-Juarrero, Mercedes, committee member
Peersen, Olve, committee member
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Abstract
In the absence of a vaccine, alternative preventative approaches against HIV-1 are needed. In pre-exposure prophylaxis (PrEP) approach, antiretroviral drugs, broadly neutralizing antibodies (bnAb) or other biological molecules are administered orally or topically for the prevention of HIV-1 infection. For successful PrEP design pharmacokinetic (PK) and pharmacodynamic (PD) studies are needed to define protective levels of antiretrovirals in mucosal tissues. The RAG-hu mice used here represent a small animal model in which human immune system is reconstituted by haematopoietic stem cells (HSC) in the immunodefficient BALB/c- Rag1-/- γc-/- and BALB/c- Rag2-/- γc-/- mice. This model was previously shown to be suitable for HIV-1 mucosal transmission and protection studies. In the experiments presented here we evaluated the utility of RAG-hu mice for the study of PK-PD aspects of antiretroviral drugs in the context of PrEP. The PK studies focused on tissue distribution of the RT inhibitor Tenofovir (TFV), the integrase inhibitor Raltegravir (RAL) and the entry inhibitor Maraviroc (MVC) following single and combinatorial oral application. Drug kinetics were examined systemically in blood plasma, and in vaginal, rectal and colonic mucosal tissues, which are the sites of HIV-1 transmission and initial viral spread. Antiretrovirals were applied in human equivalent doses to achieve steady state kinetics. Data obtained from single oral applications verified favorable PrEP profile of TFV. While results showed that RAL and MVC represent promising PrEP candidates, the data suggest that the PrEP doses would need to be higher than therapeutic ones in order to allow for once a day dosing. In combinatorial TFV/RAL and TFV/MVC oral application studies, increase in the active form of TFV (Tenofovir diphosphate, TFV-DP) accompanied by agonistic effect for the second drug in combination was observed, which can be characterized as highly favorable for PrEP applications. This is the first report on combinatorial PK of TFV, RAL and MVC in mucosal tissues which informs further testing of TFV/MVC and TFV/RAL PrEP approaches in non-human primates (NHP) and in clinical settings. For topical PrEP potential, PK profiles of TFV, RAL and MVC were also evaluated in vaginal mucosa following topical application of gel formulations. With all three drugs, one to two log higher concentrations were achieved in vaginal mucosa compared to oral application reflecting previous findings in humans. Intracellular concentrations of TFV-DP in humanized mice corresponded to the levels observed previously in human vaginal mucosa. In PD studies, the protective effect of topical PrEP with single drug and combinatorial TFV, RAL and the RT inhibitor UC781 gels was evaluated against mucosal HIV-1 transmission. High level of protection was seen with combinatorial microbicide gels - 80% (4/5) protection by TFV/UC781 gel and 87.5% (7/8) protection by TFV/RAL gel, indicating their suitability for further testing in preclinical trials. In another PD study, protective efficacy of bnAb VRC01 was examined against mucosal transmission of HIV-1 in the form of topical PrEP. The VRC01 gel (1 mg/ml) conferred protection in 77.7% (7/9) animals, while the combination of b12, 4E10, 2F5 and 2G12 bnAb which target different epitopes on the HIV-1 envelope conferred complete protection (5/5 animals) against HIV-1 mucosal transmission. These data suggest that bnAb could be effective agents for topical PrEP against HIV-1. In summary, these proof of concept PK and PD studies validated RAG-hu mouse model for preclinical evaluation of new anti-HIV-1 drugs and bnAb for oral and topical PrEP, thus providing data for further NHP studies and human clinical trials.
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Subject
HIV-1 mucosal transmission
HIV-1 pre-exposure prophylaxis
humanized mouse model
Maraviroc pharmacokinetics and pharmacodynamics
Raltegravir pharmacokinetcs and pharmacodynamics
Tenofovir pharmacokinetcs and pharmacodynamics