Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-6 (of 6 Records) |
Query Trace: Dinh CT[original query] |
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Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques
Pereira LE , Singletary T , Martin A , Dinh CT , Deyounks F , Holder A , McNicholl J , Buckheit KW , Buckheit RWJr , Ham A , Katz DF , Smith JM . Drug Deliv Transl Res 2018 8 (5) 1180-1190 This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 10(4)-10(5) ng/g, 10(5)-10(6) ng/ml, and 10(3)-10(5) ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 10(3)-10(5) ng/ml and ~ 10(2)-10(3) ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 10(1)-10(3) ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive. |
Repeated administration of high-dose depot medroxyprogesterone acetate does not alter SHIVSF162p3 viral kinetics and tenofovir pharmacokinetics when delivered via intravaginal rings
Srinivasan P , Zhang J , Dinh CT , Teller RS , McNicholl JM , Kiser PF , Herold BC , Smith JM . J Med Primatol 2017 46 (4) 129-136 BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2x105 and 1.1.x105 ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73x107 and 8.15x104 copies/mL, respectively) and cycling macaques (3.98x107 and 1.47x103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding. |
Topical delivery of tenofovir disoproxil fumarate and emtricitabine from pod-intravaginal rings protects macaques from multiple SHIV exposures
Srinivasan P , Moss JA , Gunawardana M , Churchman SA , Yang F , Dinh CT , Mitchell JM , Zhang J , Fanter R , Miller CS , Butkyavichene I , McNicholl JM , Smith TJ , Baum MM , Smith JM . PLoS One 2016 11 (6) e0157061 Topical preexposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure. Controlled, sustained release of antiretroviral (ARV) drugs may help overcome these low adherence rates if the product is protective for extended periods of time. The oral combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is currently the only FDA-approved ARV drug for HIV PrEP. A novel pod-intravaginal ring (IVR) delivering TDF and FTC at independently controlled rates was evaluated for efficacy at preventing SHIV162p3 infection in a rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques. Six macaques received pod-IVRs containing TDF (65 mg) and FTC (68 mg) every two weeks, and weekly vaginal exposures to 50 TCID50 of SHIV162p3 began one week after the first pod-IVR insertion. All pod-IVR-treated macaques were fully protected throughout the study (P = 0.0002, Log-rank test), whereas all control animals became infected with a median of 4 exposures to infection. The topical, sustained release of TDF and FTC from the pod-IVR maintained protective drug levels in macaques over four months of virus exposures. This novel and versatile delivery system has the capacity to deliver and maintain protective levels of multiple drugs and the protection observed here warrants clinical evaluation of this pod-IVR design. |
Tenofovir disoproxil fumarate intravaginal ring protects high dose depot medroxyprogesterone acetate treated macaques from multiple SHIV exposures
Smith JM , Srinivasan P , Teller RS , Lo Y , Dinh CT , Kiser PF , Herold BC . J Acquir Immune Defic Syndr 2014 68 (1) 1-5 Preclinical HIV prevention models use either a single high-dose viral challenge in depot medroxyprogesterone acetate (DMPA)-treated macaques or repeated viral challenges in cycling macaques. We tested the efficacy of an intravaginal tenofovir disoproxil fumarate (TDF) ring in a model combining repeated 30 mg injections of DMPA every 6 weeks with vaginal viral challenges weekly for 12 weeks. Twelve macaques were randomized to TDF or placebo rings. All placebo macaques became infected after a median of 2 exposures, whereas only one TDF macaque became infected at the eighth exposure (p=0.0012). The TDF ring provides durable protection in a stringent challenge model. |
Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model
Moss JA , Srinivasan P , Smith TJ , Butkyavichene I , Lopez G , Brooks AA , Martin A , Dinh CT , Smith JM , Baum MM . Antimicrob Agents Chemother 2014 58 (9) 5125-35 Pre-exposure prophylaxis using oral regimens of the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy when compared with oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described and constitutes the first report of an IVR delivering TDF and FTC, as well as a triple combination IVR delivering TDF, FTC and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study. Median steady-state drug levels in vaginal tissues were: TDF-FTC group; tenofovir (TFV, in vivo hydrolysis product of TDF), 30 mug g-1; FTC, 500 mug g-1; and TDF-FTC-MVC group; TFV, 10 mug g-1; FTC, 150 mug g-1; MVC, 20 mug g-1. No adverse events were observed and there were no toxicological findings. Mild to moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and absence of the IVRs. The IVRs did not disturb the vaginal microbiota and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation. |
Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges
Smith JM , Rastogi R , Teller RS , Srinivasan P , Mesquita PM , Nagaraja U , McNicholl JM , Hendry RM , Dinh CT , Martin A , Herold BC , Kiser PF . Proc Natl Acad Sci U S A 2013 110 (40) 16145-50 Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 x 10(5) ng/mL (range 1.1 x 10(4) to 6.6 x 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans. |
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