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Rectal Tenofovir Gel Yields Much Higher Rectal
and Vaginal Levels Than Oral Tenofovir
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- "A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate"
15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19-21, 2014, Washington, DC
15th Intl Wrkshp Clinical Pharm HIV Therapy A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate - (05/22/14)
15th Intl Wrkshp Clinical Pharm HIV Therapy Estimated Time to Protection and Duration of Protection With Daily TDF/FTC PrEP - (05/21/14)......may fully protect a person from HIV after 7 days of dosing.....following daily dosing to steady state a high level of protection may last for several days after the last dose is taken.....Authors comment: We think the important conclusion is 7 days of dosing appears sufficient to reach therapeutic drug concentrations for MSM. We think that the "duration of action" (ie drug concentrations lingering after dosing stops) may be more difficult to interpret because people should not stop dosing while they may be being exposed to HIV.
Mark Mascolini
Tenofovir 1% gel applied rectally yielded rectal tissue concentrations orders of magnitude greater than those achieved with oral tenofovir, according to results of an 18-person study by US researchers [1]. Systemic tenofovir exposure was lower with 1% gel than with oral tenofovir, but vaginal exposure was greater with the rectal gel.
Oral tenofovir regimens have proved effective in preventing HIV in heterosexual women and men, men who have sex with men, and injection drug users--as long as trial participants take their pills on schedule or close to schedule. RMP-02/MTN-006 is the first trial to measure human rectal pharmacokinetics of topically applied tenofovir in multiple compartments, including rectal and vaginal tissue, rectal and vaginal fluid, peripheral blood mononuclear cells (PBMCs), mucosal mononuclear cells, and plasma [2] (http://clinicaltrials.gov/ct2/show/NCT00984971).
University of North Carolina (UNC) researchers enrolled 14 men and 4 women who received a single 300-mg oral dose of tenofovir disoproxil fumarate then got randomized 2-to-1 to (1) single then daily rectal 1% vaginal gel (for 7 days) or (2) single than daily placebo gel. A 2-week washout separated each of the three dosing intervals. Participants gave samples of blood, rectal and vaginal mucosal fluids, and colorectal biopsies (0.5 and 24 hours after dosing). The investigators measured extracellular tenofovir concentrations in plasma, rectal and vaginal fluids, and tissue; they measured the active metabolite tenofovir diphosphate (TFVdp) in tissue, PBMCs, and mucosal mononuclear cells.
Tenofovir plasma levels were 24- to 33-fold lower and plasma half-life was 5 hours shorter after a single rectal application of 1% tenofovir gel than after a single oral dose (P = 0.02). Rectal tissue concentrations of both tenofovir and TFVdp were 100 to 10,000 times higher after a single rectal dose than after a single oral dose. TFVdp levels in rectal tissue were significantly higher after multiple rectal doses than after a single rectal dose (P < 0.05). In mucosal mononuclear cells, TFVdp concentrations were orders of magnitude higher after a single rectal dose or multiple rectal doses than after a single oral dose.
TFVdp levels in mucosal mononuclear cells correlated positively with rectal tissue TFVdp in both CD4-positive and negative rectal tissue mononuclear cells (residual standard error [RSE] 0.46). The UNC researchers calculated 60% higher tenofovir phosphorylation in CD4-positive than negative cells. Rectal fluid tenofovir correlated with plasma tenofovir (RSE 0.38), rectal tissue tenofovir (RSE 0.67), and rectal tissue TFVdp (RSE 0.66).
Rectal dosing yielded 72% higher vaginal penetration than did oral dosing. And after single and multiple rectal dosing, vaginal fluid tenofovir correlated with plasma tenofovir (RSE 0.44).
The UNC team concluded that rectal tenofovir gel "delivers lower systemic exposure and higher vaginal exposure than do similar doses of oral delivery, with rectal tissue accumulation of TFVdp over time, likely due to the long intracellular half-life." Because rectal tenofovir fluid concentration correlated with tissue concentration, they proposed that rectal swabs "may be reasonable bio-indicators of rectal tissue/cell concentrations, providing coarse but less-invasive methods to estimate adherence and TFV concentrations in target tissues."
References
1. Yang KH, Hendrix C, Bumpus N, et al. A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 19-21, 2014. Washington, DC. Abstract O_09.
2. Anton PA, Cranston RD, Kashuba A, et al. RMP-02/MTN-006: a phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses. 2012;28:1412-1421. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484811/
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