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Antimicrob Agents Chemother. 2010 June; 54(6): 2744–2745.
Published online 2010 March 22. doi:  10.1128/AAC.00241-10
PMCID: PMC2876424

Raltegravir Penetration in Seminal Plasma of Healthy Volunteers[down-pointing small open triangle]

Penetration of antiretroviral drugs into the genital tract is crucial for virological efficacy in this compartment and impacts the transmission of the virus. Anti-HIV drugs showed different degrees of passage into the male and female genital systems, and their efficacy appeared related to the concentrations reached at the site of action (2, 5).

Raltegravir (RGV) is a novel drug whose target is the HIV preintegrase complex. Jones and colleagues demonstrated a significant passage in the cervicovaginal fluid of female healthy volunteers, with concentrations around 93% of plasma and a longer elimination half-life (17 versus 7 h) (4). A paper recently published in this journal showed that males treated with RGV-containing regimens had undetectable viral loads in seminal plasma and showed variable but high drug penetration in such compartment. The median RGV concentration in semen measured at 5 h postdose was 345 (range, 83 to 707) ng/ml with a median semen-to-plasma RGV concentration ratio of 1.42 (range, 0.52 to 6.66) (1). However, no data of RGV penetration in seminal plasma over the whole dosing interval are currently available.

We performed a multiple-dose, one-way, open-labeled, noncontrolled, single-center study. Eight healthy male volunteers were enrolled after we obtained written informed consent. Median (interquartile range [IQR]) age, weight, and body mass index (BMI) were 31 (28 to 39) years, 79 (75 to 89) kg, and 24.5 (22.3 to 26.3) kg/m2, respectively. Subjects were considered healthy according to history, physical examination, electrocardiogram, and standard laboratory tests, including a test for hepatitis viruses and an HIV screen. Subjects were administered RGV (400 mg twice daily) in fed state for 4 days plus a single dose on day 5. On day 5, peripheral blood and semen (after 5 days of sexual abstinence) were concomitantly collected within 11 to 12 h (4 subjects) or 2 to 4 h (4 subjects) after last RGV dose intake. RGV blood plasma and seminal plasma levels were measured by a validated high-performance liquid chromatography (HPLC-PDA) method with limit of detection of 11.7 ng/ml (3). Results were expressed as geometric mean (95% confidence interval).

In the group with measurements performed at the end of the dosing interval, blood and semen RGV concentrations were 151 (51 to 443) and 937 (212 to 3,582) ng/ml, respectively, with a semen-to-blood plasma concentration ratio of 6.45 (3.78 to 9.37) (Fig. (Fig.1)1) . In the group where RGV was measured after recent drug intake (2 to 4 h), plasma and semen concentrations were 651 (438 to 1,020) and 953 (541 to 1,706) ng/ml, respectively, with a semen-to-blood plasma ratio of 1.62 (1.33 to 2.06). All samples were found to be above the 95% inhibitory concentration of wild-type HIV-1 strains (14.6 ng/ml).

FIG. 1.
Scatter-dot representation of plasma (filled markers) and seminal (empty markers) concentrations (ng/ml) over time. A single patient's concentrations are represented with the same symbol.

Our study confirmed a high and variable degree of RGV penetration in seminal plasma. However, we showed for the first time that the magnitude of penetration significantly varies over the dosing interval. The semen-to-blood plasma concentration ratio, in fact, was higher at the end of the dosing interval (6.45) than at 2 to 4 h after drug intake (1.62). This finding suggests a possible delay of drug penetration from plasma to semen and/or a slower RGV clearance in the compartment, leading to increasing levels in semen over time compared to stable plasma concentrations (equivalent mean plasma levels in the two groups). The possible therapeutical and prophylactic implications warrant study in the clinical setting.

Footnotes

[down-pointing small open triangle]Published ahead of print on 22 March 2010.

REFERENCES

1. Barau, C., C. Delaugerre, J. Braun, N. de Castro, V. Furlan, I. Charreau, L. Gérard, C. Lascoux-Combe, J. M. Molina, and A. M. Taburet. 2010. High concentration of raltegravir in semen of HIV-infected men: results from a substudy of the EASIER-ANRS 138 trial. Antimicrob. Agents Chemother. 54:937-939. [PMC free article] [PubMed]
2. Chan, D. J. 2005. Pathophysiology of HIV-1 in semen: current evidence for compartmentalisation and penetration by antiretroviral drugs. Curr. HIV Res. 3:207-222. [PubMed]
3. D'Avolio, A., L. Baietto, M. Siccardi, M. Sciandra, M. Simiele, V. Oddone, S. Bonora, and G. Di Perri. 2008. An HPLC-PDA method for the simultaneous quantification of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse transcriptase inhibitor etravirine, and 11 other antiretroviral agents in the plasma of HIV-infected patients. Ther. Drug Monit. 30:662-669. [PubMed]
4. Jones, A. E., J. A. Talameh, K. B. Patterson, N. L. Rezk, H. A. Prince, and A. D. M. Kashuba. 2009. First-dose and steady-state pharmacokinetics of raltegravir in the genital tract of HIV negative women, abstr. O-06. Abstr. 10th Int. Workshop Clin. Pharmacol. HIV Ther., Amsterdam, Netherlands, 15 April to 1 May 2009.
5. Kalichman, S. C., G. Di Berto, and L. Eaton. 2008. Human immunodeficiency virus viral load in blood plasma and semen: review and implications of empirical findings. Sex. Transm. Dis. 35:55-60. [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)