NATAP/PK-Wkp: Rilpivirine PrEP for Men/Women

[Guest guest]

Subject: NATAP/PK-Wkp: Rilpivirine PrEP for Men/Women

Injected Rilpivirine for

PrEP Stays in Plasma for 84 Days in Women and Men

13th International Workshop on Clinical Pharmacology of HIV Therapy, April

16-18, 2012, Barcelona

Mark Mascolini

A single 600-mg intramuscular dose of the nonnucleoside rilpivirine remained in

the circulation for 84 days in 10 women and 6 men without HIV [1]. Vaginal

tissues levels of rilpivirine were slightly lower than cervicovaginal fluid

levels, whereas male rectal tissue rilpivirine concentrations were higher than

rectal fluid levels. The findings suggest that intermittently injected

rilpivirine could be effective pre-exposure prophylaxis (PrEP), if the

concentrations maintained protect against HIV.

Studies of daily tenofovir/emtricitabine for PrEP showed that the strategy substantially

lowers the risk of HIV acquisition in women and men, as long as the drugs are

taken regularly [2-5]. In one trial high-risk African women randomized to take

tenofovir/emtricitabine PrEP or placebo adhered poorly and were not protected

from HIV [5]. Because rilpivirine has a long half-life, University of Liverpool

and St. 's Centre investigators planned this study to determine how long

concentrations of a long-acting rilpivirine nanosuspension persist in plasma

and genital compartments.

This open-label exploratory pharmacokinetic trial involved 10 women and 6 men

without HIV infection and with a low behavioral HIV risk. Eight of the women

were African in ancestry, 1 was white, and 1 was Asian. Five men where white

and 1 African. Median ages were 37 in women and 40 in men.

Study participants received a single 600-mg shot of rilpivirine G001

long-acting nanosuspension in the gluteus maximus and had plasma samples

collected regularly for the next 84 days. Study participants also routinely

collected cervicovaginal fluid by direct aspiration or rectal fluid by

intra-rectal aspiration with Weck Cel spears. Vaginal tissue biopsies were done

14 days or 7 and 28 days after the injection, and rectal tissue biopsies were

done in men 7 and 14 days after the injection.Rilpivirine concentrations persisted in plasma in women and

men for 84 days at the following geometric mean (and 90% confidence interval)

concentrations:

-- 84-day area under the concentration-time curve (AUC84d): 3673 ng*day/mL

(3039-4307) in women and 4555 ng*day/mL (3720-5391) in men

-- Concentration on day 84 (C84d): 16.5 ng/mL (12.3-20.6) in women and 20.1

ng/mL (16.0-24.3) in men

-- Maximum concentration (Cmax): 98.4 ng/mL (81.6-115.2) in women and 131.7

ng/mL (102.5-160.8) in men

-- Time to maximum concentration: 6.9 days (2.1-11.9) in women and 4.6 days

(3.4-5.7) in men

-- Terminal half-life: 35.3 days (24.4-41.4) in women and 32.9 days (24.4-41.4)

in men

In women rilpivirine cervicovaginal fluid/plasma ratios were 1.21 (0.88-1.53)

for AUC84d, 1.41 (0.91-1.91) for C84d, and 1.23 (0.86-1.60) for Cmax. Vaginal

tissue/plasma ratios were 0.68 (0.53-0.84) on day 7, 0.75 (0.57-0.93) on day

14, and 1.09 (0.54-1.69) on day 28.

In men rilpivirine rectal fluid/plasma ratios were 0.21 (0.11-0.31) for AUC84d,

0.07 (0.03-0.17) for C84d, and 0.28 (0.19-0.36) for Cmax. Rectal tissue/plasma

ratios were 0.92 (0.82-1.02) on day 7 and 0.89 (0.65-1.14) on day 14.

Rilpivirine concentrations were slightly lower in vaginal tissue than in

cervicovaginal fluid (VT/CVF ratio 0.73-1.01), whereas in men concentrations

were higher in rectal tissue than in rectal fluid (RT/RF ratio 3.88-6.32).

Summing up, for women rilpivirine accumulation was greatest in vaginal fluid

followed by plasma, which was equivalent with vaginal tissue. In men rilpivirine

accumulation was greatest in rectal tissue, followed by plasma, followed by

rectal fluid. Overall, men had about 25% higher rilpivirine plasma exposure

than women.

The Liverpool team noted that "further studies are required to determine

the safety and pharmacokinetics of long-acting rilpivirine following multiple

dosing and to determine whether the concentrations achieved at these

transmission sites are adequate to prevent infection."

References

1. Else L, 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.

2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among

heterosexual men and women. 19th Conference on Retroviruses and Opportunistic

Infections. March 5-8, 2012. Seattle. Abstract 29.

3. Donnell D, Baeten J, C Hendrix C, et al. Tenofovir disoproxil fumarate drug

levels indicate PrEP use is strongly correlated with HIV-1 protective effects:

Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections.

March 5-8, 2012. Seattle. Abstract 30. http://www.natap.org/2012/CROI/croi_15.htm.

4. P, Liu A, Buchbinder S, et al. Intracellular tenofovir-DP

concentrations associated with PrEP efficacy in MSM from iPrEx. 19th Conference

on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle.

Abstract 31LB.

5. Van Damme L, Corneli A, Ahmed K, et al. The FEM-PrEP trial of

emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th

Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012.

Seattle. Abstract 32LB. http://www.natap.org/2012/CROI/croi_19.htm.