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Raltegravir Levels in Cervicovaginal Fluid May Prompt PEP and PrEP Studies
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10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Raltegravir area-under-the curve level in cervicovaginal fluid (CVF) was equivalent to blood levels after multiple doses in HIV-negative volunteers [1]. And half-life of the integrase inhibitor was more than twice as long in CVF as in blood. These findings and others led Amanda Jones and University of North Carolina colleagues to propose that raltegravir should be evaluated for postexposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) in women.
In this first study of raltegravir in the genital tract, 7 healthy volunteers without HIV took an observed 400-mg dose of raltegravir twice daily for 6 days and a single dose on day 7. The first dose began 5 to 7 days after completion of menses. All women were premenopausal and using at least one form of contraception. None of them had a sexually transmitted infection. They gave 9 paired blood and CVF samples after the first dose, then more than 12 hours after dosing on days 3 through 6. On day 7 they gave 9 paired samples after dosing, then 24 and 48 hours after the last dose. They took each dose with a 545 kcal meal that was 70% carbohydrate, 18% fat, and 12% protein.
All 7 women were white, their median age was 21 (range 19 to 46) and median weight 65 kg (range 52.3 to 72.9). Four women were taking combination oral contraceptives.
On the first day of dosing, median (and interquartile range [IQR]) raltegravir maximum concentration (Cmax) measured 790 (249-2565) ng/mL in blood, time to maximum concentration (Tmax) was 6 (3-6) hours, 12-hour concentration (C12h) was 55 (10-255) ng/mL, and 0-to-12-hour area under the curve (AUC) was 3393 (717-7322) ng/hour/mL.
Raltegravir became detectable in CVF 6 hours after the first dose and reached a Cmax of 631 (327-1568) ng/mL, with a Tmax of 12 (8-12) hours, a C12h of 607 (321-1283) ng/mL, and an AUC of 1677 (910-66,716) ng/hour/mL. Jones noted that raltegravir entry into the female genital tract is slower than that of other antiretrovirals, but 5 of 7 women had detectable levels within 12 hours. Steady-state dynamics were reached after 2 days in blood and after 4 days in CVF.
On dosing day 7, median (and IQR) raltegravir Tmax was faster in CVF than in blood, C12h was higher in CVF, and Cmax and AUC were equivalent in blood and CVF:
&183; Cmax 1874 (403-2200) ng/mL in blood and 1272 (879- 2388) in CVF
&183; Tmax 8 (6-12) hours in blood and 3 (0.5-3) hours in CVF
&183; C12h 19 (10-31) ng/mL in blood and 282 (142-523) ng/mL in CVF
&183; AUC 11,911 (6979-15998) ng/hour/mL in blood and 9769 (2238-19,649) ng/hour/mL in CVF
CVF-to-blood ratios for AUC on days 1 and 7 were 0.64 (IQR 0.26-1.91) and 0.93 (IQR 0.41-1.69). Raltegravir terminal half-life was 7 (5-12) hours in blood and 17 (14-23) hours in CVF. Two days after the last dose, raltegravir concentrations in CVF were about 50% of the blood concentration 12 hours after dosing.
Jones compared these results with previous research on antiretroviral exposure in CVF [2]. Six drugs attain higher concentrations in CVF than blood: maraviroc (CVF level 410% of blood level), lamivudine (400%), emtricitabine (375%), indinavir (200%), tenofovir (110%), and zidovudine (235%). Eleven antiretrovirals achieve lower concentrations in CVF: nevirapine (80%), amprenavir (50%), ritonavir (26%), didanosine (21%), delavirdine (20%), atazanavir (18%), lopinavir (18%), abacavir (8%), stavudine (5%), efavirenz (0.4%), and saquinavir (not detectable).
The investigators suggested that "the pharmacology of raltegravir in CVF may be favorable for further investigation as an agent of HIV prophylaxis."
References
1. Jones A, Talameh J, Patterson K, Rezk N, Prince H, Kashuba A. First-dose and steady-state pharmacokinetics (PK) of raltegravir (RAL) in the genital tract (GT) of HIV uninfected women. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract O_06.
2. Dumond JB, Yeh RF, Patterson KB, et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS. 2007;21:1899-1907.
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