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  15th International Workshop on
Clinical Pharmacology
of HIV and Hepatitis Therapy
May 19- 21, 2014, Washington, DC
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Maraviroc and Raltegravir Quickly Distributed in Female Genital Tract
  15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19- 21, 2014, Washington, DC
Mark Mascolini
Both maraviroc and raltegravir get distributed through the female genital tract about 6 hours after oral dosing, according to results of a single-dose study in 48 healthy women [1]. Maximum concentration of both antiretrovirals was substantially higher in rectal tissue than in vaginal or cervical tissue after oral dosing.
Trials of once-daily preexposure prophylaxis (PrEP) with tenofovir/emtricitabine show that good adherence is essential to this HIV prevention strategy. Two of the trials--VOICE [2] and FEM-PrEP [3]--found that high adherence to a daily oral drug proved too difficult for most study participants. But University of North Carolina (UNC) researchers observed that adherence requirements may differ by drug exposure site. For example, tenofovir accumulates at much higher levels in male rectal tissue than in cervical or vaginal tissue. They conducted this trial as a step to determining whether intermittent or as-needed dosing strategies can prevent HIV with antiretroviral-based PrEP (http://clinicaltrials.gov/ct2/show/NCT01330199).
The UNC team enrolled healthy 18- to 49-year-old women with intact gastrointestinal and genital tracts, regular menstrual cycles, and a normal Pap smear history. They excluded pregnant or lactating women and those with a positive urine drug screen. Volunteers received single oral doses of maraviroc or raltegravir at 50%, 100%, or 200% of the licensed doses, with 8 or 9 women taking each dose. The researchers collected 13 plasma samples in the 48 hours after dosing and vaginal, cervical, and rectal tissue samples 6, 12, 24, and 48 hours after dosing.
Two thirds of women in the maraviroc group and three quarters in the raltegravir group were Caucasian, 29% and 17% were African American, age averaged 27 and 22 years, and body mass index averaged 24.1 and 22.5 kg/m(2). Researchers had results for all but one woman in each study arm. All adverse events were grade 1, and event rates were not greater among women taking the 200% dose.
Because maraviroc and raltegravir exposure did not differ in vaginal tissue or cervical tissue, the researchers combined vaginal and cervical exposure data for the two drugs in their analyses. Both antiretrovirals became rapidly distributed to vaginal/cervical tissue at a medium time to maximum concentration (Tmax) of 6 hours. Maraviroc attained rectal tissue distribution 4 times faster than raltegravir (median Tmax 6 versus 24 hours).
Median maximum concentrations (Cmax) in vaginal/cervical tissues were 53, 351, and 535 ng x g(-1) for the 50%, 100%, and 200% doses of maraviroc and 127, 329, and 274 ng x g(-1) for the raltegravir doses. Respective Cmax values in rectal tissue were 740, 1201, and 4749 ng x g(-1) for maraviroc and 151, 9893, and 4394 ng x g(-1) for raltegravir.
Rectal tissue Cmax was about 8 times higher than vaginal/cervical tissue Cmax for maraviroc and about 15 times higher for raltegravir. Rectal area under the concentration-time curve (AUC) was about 10 times higher in rectal than vaginal/cervical tissue for maraviroc and about 25 times higher for raltegravir.
The UNC investigators charted a linear (but not dose-proportional) relationship between maraviroc dose and AUC in cervical/vaginal tissue and rectal tissue. They also saw a linear (but not dose-proportional) relationship between raltegravir dose and AUC in cervical/vaginal tissue but not in rectal tissue, where AUC hit a plateau at higher doses. Vaginal/cervical concentrations correlated with plasma concentrations for maraviroc (r2 = 0.72, P < 0.001) and for raltegravir (r2 = 0.76, P < 0.001). But rectal tissue concentrations did not correlate with plasma levels for either antiretroviral.
The researchers concluded that rapid distribution of maraviroc and raltegravir in the female genital tract makes them "potentially well-suited for chemoprophylaxis in women." They plan to use these tissue findings to conduct pharmacokinetic modeling and simulation studies of intermittent PrEP for women.
1. Cottrell ML, Prince HMA, Sykes C, et al. Mucosal tissue pharmacokinetics of maraviroc and raltegravir in women: implications for chemoprophylaxis. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 19-21, 2014. Washington, DC. Abstract O_08.
2. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 26LB. http://www.natap.org/2013/CROI/croi_09.htm
3. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422. www.natap.org/2012/HIV/nejmoa1202614.pdf