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Gender and Weight Affect Long-Acting Rilpivirine Levels in Healthy Volunteers
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14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam
Mark Mascolini
Women and people with a higher body mass index (BMI) attained lower plasma concentrations of injected long-acting rilpivirine (RPV-LA), a once-monthly preexposure prophylaxis (PrEP) candidate [1]. In women, younger age and higher BMI predicted lower rilpivirine levels in cervicovaginal fluid.
Previous work showed that one 600-mg intramuscular dose of the nonnucleoside rilpivirine remained in circulation for 84 days in 10 women and 6 men without HIV [2], findings suggesting that intermittently injected rilpivirine could provide a simple PrEP regimen with easy adherence. UK researchers conducted this analysis of rilpivirine concentrations in 60 women and 6 men, all of them healthy HIV-negative volunteers. Women received 300, 600, or 1200 mg of intramuscular RPV-LA (20 women per dose), and all men got the 600-mg dose.
The Liverpool/London team collected plasma samples at 0, 4, and 8 hours on day 0 and at the same intervals between days 1 and 84. They measured rilpivirine levels in self-collected cervicovaginal fluid. To measure rilpivirine levels in vaginal tissue or rectal tissue (men only), the researchers took biopsies at two points on day 7, 14, 28, or 56.
Of the 66 study participants, 29 were black African or Caribbean, 30 were white, and 7 had a different racial/ethnic background. In women, median (range) weight measured 66.2 kg (47.8 to 100.4) and median (range) body mass index 23.6 kg/m2 (17.1 to 34.7). Respective measures in men were 76.3 kg (61.0 to 95.0) and 24.6 kg/m2 (20.4 to 30.0). Median age was older in men (39.5 years, range 27.2 to 41.0) than women (29.3 years, range 18.3 to 48.9). Neither BMI nor age differed significantly between women and men.
In women geometric mean plasma area under the concentration-time curve for 84 days (AUC84d) was 1231.0 ng x day/mL with 300 mg, 2934 ng x day/mL with 600 mg, and 5981.6 ng x day/mL with 1200 mg. Respective cervicovaginal fluid AUC84d values were 2027.1, 3207.3, and 6499.5 ng x day/mL. In comparison, male plasma AUC84d with 600 mg was 3873 ng x day/mL, 32% higher than with the 600-mg dose in women. At the 600-mg dose, rectal versus vaginal geometric mean AUC84d was 935 versus 3207.3 ng x day/mL (70% lower in rectal tissue).
Female gender was independently associated with lower rilpivirine plasma maximum concentration (-32.2%, P = 0.013), while higher BMI was associated with lower rilpivirine maximum concentration (-2.3%, P = 0.028). Female gender was also independently associated with lower plasma AUC84d (-28.1%, P = 0.032). BMI was not associated with AUC84d. Nor did age or ethnicity affect systemic rilpivirine pharmacokinetics.
Women younger than 40 had significantly lower rilpivirine AUC84d in cervicovaginal fluid than did older women (-34.4%, P = 0.010). And BMI at or above 25 kg/m2 (versus lower) was associated with significantly lower rilpivirine AUC84d in cervicovaginal fluid (-35.4%, P = 0.005). Higher BMI was also associated with lower vaginal tissue rilpivirine at day 14 (-57.9%, P < 0.001).
The researchers suggested the impact of gender on rilpivirine plasma exposure could reflect differences in adipose tissue distribution in women and men. Although younger age and higher BMI lowered rilpivirine levels in vaginal fluid, the investigators noted that "changes in pH due to the stage of the menstrual cycle, level of mucus production and permeability of the vaginal epithelium, throughout the study duration, are also likely to impact on drug distribution in the female genital tract."
References
1. Else L, Jackson A, Egan D, et al. Effects of gender, race, age and BMI on the pharmacokinetics of long-acting rilpivirine (RPV-LA) after a single IM injection in HIV-negative subjects. 14th International Workshop on Clinical Pharmacology of HIV Therapy, April 22-24, 2013, Amsterdam. Abstract O_01.
2. Else L, Jackson A, Tjia J, et al. Pharmacokinetics of long-acting rilpivirine in plasma, genital tract and rectum of HIV-negative females and males administered a single 600 mg dose. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_12. http://www.natap.org/2012/pharm/Pharm_06.htm
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