Placental Transfer of Rilpivirine in anEx VivoHuman Cotyledon Perfusion Model

ABSTRACTPlacental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ± 8% (mean ± standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ± 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.

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Placental Transfer of Darunavir in anEx VivoHuman Cotyledon Perfusion Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03184-14 ◽

2014 ◽

Vol 58 (9) ◽

pp. 5617-5620 ◽

Cited By ~ 8

Author(s):

Laurent Mandelbrot ◽

Dominique Duro ◽

Emilie Belissa ◽

Gilles Peytavin

Keyword(s):

Steady State ◽

Standard Deviation ◽

Protease Inhibitor ◽

Transfer Rate ◽

Placental Transfer ◽

Hiv Protease ◽

Fetal Exposure ◽

Perfusion Model ◽

The Mean ◽

Low Rate

ABSTRACTPlacental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (± the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0% ± 2.1%, and the mean (±SD) clearance index (darunavir FTR/antipyrine FTR) was 40.3% ± 5.8%. This shows that darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.

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Bidirectional Transfer of Raltegravir in anEx VivoHuman Cotyledon Perfusion Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00007-16 ◽

2016 ◽

Vol 60 (5) ◽

pp. 3112-3114 ◽

Cited By ~ 6

Author(s):

Cécile Vinot ◽

Jean-Marc Tréluyer ◽

Carole Giraud ◽

Laurent Gavard ◽

Gilles Peytavin ◽

...

Keyword(s):

Standard Deviation ◽

Transfer Rate ◽

Placental Transfer ◽

Integrase Inhibitor ◽

Hiv Integrase ◽

Perfusion Model ◽

The Mean

ABSTRACTPlacental transfer of the HIV integrase inhibitor raltegravir (RLT) was investigated in term human cotyledons in the maternal-to-fetal (n= 3) and fetal-to-maternal (n= 6) directions. In the maternal-to-fetal direction, the mean ± standard deviation (SD) fetal transfer rate (FTR) was 9.1% ± 1.4%, and the mean ± SD clearance index (IC), i.e., RLT FTR/antipyrine FTR, was 0.28 ± 0.05. In the fetal-to-maternal direction, the mean ± SD CI was 0.31 ± 0.09. Placental transfer of RLT was high in both directions.

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Pharmacokinetic and Safety Evaluation of BILR 355, a Second-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00363-08 ◽

2008 ◽

Vol 52 (12) ◽

pp. 4300-4307 ◽

Cited By ~ 16

Author(s):

Fenglei Huang ◽

Michael Koenen-Bergmann ◽

Thomas R. MacGregor ◽

Arne Ring ◽

Susan Hattox ◽

...

Keyword(s):

Reverse Transcriptase ◽

Healthy Volunteers ◽

Maximum Concentration ◽

Second Generation ◽

Dose Range ◽

Transcriptase Inhibitor ◽

Time Curve ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

The Mean ◽

Reverse Transcriptase Inhibitor

ABSTRACT BILR 355 is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) under clinical development for the treatment of human immunodeficiency virus infection, particularly in those who harbor virus resistant to the currently available NNRTIs. Two single-center, double-blinded, placebo-controlled, parallel dose-escalation studies were conducted to evaluate the pharmacokinetics and safety of oral BILR 355 administration alone and after coadministration with ritonavir (RTV) at 100 mg. Following a single dose of BILR 355 in oral solution, the mean half life (t 1/2) was 2 to 4 h, with peak concentrations occurring at 0.5 to 1 h postadministration. The mean apparent clearance (CL/F) ranged from 79.2 to 246 liters/h for administered doses of 12.5 mg to 100 mg. This observed nonlinearity in CL/F resulted from the increased bioavailability attributed to a saturated absorption and/or elimination process at higher doses. In contrast, after the coadministration of single doses of 5 mg to 87.5 mg of BILR 355 with RTV, the mean CL/F ranged from 5.88 to 8.47 liters/h. Over the dose range (5 to 87.5 mg) studied, systemic BILR 355 exposures were approximately proportional to the doses administered when they were coadministered with RTV. With RTV coadministration, the mean t 1/2 increased to 10 to 16 h, and the mean time of the maximum concentration in plasma lengthened to 1.5 to 5 h. Compared to the values for BILR 355 given alone, the mean area under the concentration-time curve from time zero to infinity, the maximum concentration in plasma, and the t 1/2 of BILR 355 achieved after coadministration with RTV increased 15- to 30-fold, 2- to 5-fold, and 3- to 5-fold, respectively. In both studies, BILR 355 appeared to be safe and well tolerated in healthy volunteers when the outcomes in the treated volunteers were compared with those in the placebo group.

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High Rate Multiple Drug Resistances in HIV-Infected Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor Regimens in Thailand, Where Subtype A/E is Predominant

Journal of the International Association of Physicians in AIDS Care ◽

10.1177/1545109706294288 ◽

2006 ◽

Vol 5 (4) ◽

pp. 152-156 ◽

Cited By ~ 14

Author(s):

Ploenchan Chetchotisakd ◽

Siriluck Anunnatsiri ◽

Sasisopin Kiertiburanakul ◽

Ruengpung Sutthent ◽

Thanomsak Anekthananon ◽

...

Keyword(s):

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

High Rate ◽

Multiple Drug ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Subtype A ◽

Reverse Transcriptase Inhibitor

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Pharmacokinetic Effects of Coadministration of Lersivirine with Raltegravir or Maraviroc in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00572-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 887-892 ◽

Cited By ~ 4

Author(s):

Manoli Vourvahis ◽

Grant Langdon ◽

Robert R. LaBadie ◽

Gary Layton ◽

Marie-Noella Ndongo ◽

...

Keyword(s):

Steady State ◽

Integrase Inhibitor ◽

Transcriptase Inhibitor ◽

Time Profile ◽

Maximum Plasma ◽

Open Label ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Cyp3a4 Enzyme ◽

Reverse Transcriptase Inhibitor ◽

Drug Resistant Strains

ABSTRACTLersivirine (UK-453,061) is a new nonnucleoside reverse transcriptase inhibitor currently being developed as a treatment for human immunodeficiency virus type 1 infection. Lersivirine shows potent activity against wild-type and clinically relevant drug-resistant strains. Previous studies have demonstrated that lersivirine is metabolized by glucuronidation via UGT2B7 and by cytochrome P450 3A4 (CYP3A4). Lersivirine is also a weak inducer of the CYP3A4 enzyme. Therefore, coadministered lersivirine could potentially affect the pharmacokinetics of maraviroc, a CCR5 antagonist metabolized by CYP3A4, and raltegravir, an integrase inhibitor metabolized by glucuronidation. Two open-label studies assessed the pharmacokinetics of raltegravir and of maraviroc when they were coadministered with lersivirine and the pharmacokinetics of lersivirine when it was coadministered with raltegravir. Minor, clinically nonsignificant effects on the pharmacokinetics of raltegravir coadministered with lersivirine were observed at steady state for raltegravir, with estimated mean changes of −15%, −29%, and +25% in the area under the concentration-time profile from time zero to the end of the dosing interval (AUCtau), maximum plasma concentration (Cmax), and concentration observed 12 h postdose (C12), respectively. There were no clinically relevant effects of steady-state raltegravir on lersivirine AUCtau,Cmax, or concentration observed 24 h postdose (C24) (estimated mean changes of −2 to +5%). Coadministration of lersivirine at steady state with maraviroc resulted in no clinically relevant effects on maraviroc AUCtau,Cmax, orC12(estimated mean changes of +3.4 to +8.6%). Lersivirine appeared to be generally well tolerated in these studies and appears to be suitable for coadministration with raltegravir or maraviroc without the need for dose modification.

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