The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Angela D M Kashuba - One of the best experts on this subject based on the ideXlab platform.
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randomized pharmacokinetic crossover study comparing 2 curcumin preparations in plasma and Rectal Tissue of healthy human volunteers
The Journal of Clinical Pharmacology, 2017Co-Authors: Gary Asher, Angela D M Kashuba, Ruin Moaddel, Mitesh Sanghvi, Katina Sourou Sylvestre Dossou, Robert S Sandler, Roy L HawkeAbstract:Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and Tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and Rectal Tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, Tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and Rectal Tissues.
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correlation between compartmental tenofovir concentrations and an ex vivo Rectal biopsy model of Tissue infectibility in the rmp 02 mtn 006 phase 1 study
PLOS ONE, 2014Co-Authors: Nicola Richardsonharman, Ian Mcgowan, Craig W Hendrix, Namandje N Bumpus, Christine K Mauck, Ross D Cranston, Kuo Yang, Julie Elliott, Karen Tanner, Angela D M KashubaAbstract:Objectives: This study was designed to assess the dose-response relationship between Tissue, blood, vaginal and Rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and ex vivo Rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and Rectal administration of TFV 1% vaginally-formulated gel. Design: Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females. Methods: Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2:1 to receive a single then seven-daily Rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and Rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and ex vivo HIV-1 challenge. Results: There was a significant fit for the TFVdp dose-response model for Rectal Tissue (p=0.0004), CD4 + MMC (p,0.0001), CD4 2 MMC (p,0.0001), and TotalMMC (p,0.0001) compartments with r 2 ranging 0.36–0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC50 of Rectal Tissue TFVdp predicted to be necessary to suppress HIV in Rectal Tissue. The EC50 for CD4 + MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided in-vivo doses predicted to provide for 50% efficacy in the ex vivo assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC90 biopsy efficacy for CD4 2 MMC, CD4 + MMC and TotalMMC compartments. Conclusion: The TFVdp MMC compartment (CD4+, CD42 and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression. ClinicalTrials.gov NCT00984971.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:BACKGROUND Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions. METHODS A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One Rectal Tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal Tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions.
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pre exposure prophylaxis for hiv prevention how to predict success
The Lancet, 2012Co-Authors: Angela D M Kashuba, Kristine B Patterson, Julie B Dumond, Myron S CohenAbstract:Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052,1 showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 0042 and VOICE3), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX,4 TDF2,5 Partners in Prevention [PIP],6 and Fem-PrEP7), and two used oral TDF alone (VOICE3 and PIP6). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004,2 iPrEx,4 TDF2,5 and PIP6) and of futility (VOICE3 and Fem-PrEP7). Table Antiretroviral-based HIV prevention studies Clearly, results on pre-exposure prophylaxis will be used to inform policy and to plan future research, and so the trials’ findings need to be considered carefully. There were key differences in the pre-exposure prophylaxis trials (table): each included different populations with distinct routes of HIV transmission. For example, iPrEx4 was the first success for oral pre-exposure prophylaxis and focused on men who have sex with men. It is reasonable to assume that anal intercourse was the key route of transmission in the iPrEx trial,4 and was less frequently the source of HIV infection in the heterosexual women and men in the Fem-PrEP,7 VOICE,3 TDF2,5 and PIP6 studies. HIV acquisition is more efficient after anal intercourse,8 and more HIV variants are acquired during anal intercourse than cervicovaginal exposure.9 We have reported substantial differences in anti-retroviral drug concentrations in mucosal Tissues.10–12 After oral administration of co-formulated TDF and FTC, there were 100-fold higher concentrations of tenofovir in Rectal Tissue compared with cervicovaginal Tissue.12 Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine (FTC-TP) are required to inhibit HIV replication.12 100-fold higher concentrations of TFV-DP were detected in the rectum as compared with cervix and vagina.12 Conversely, FTC-TP concentrations were 10–15 fold higher in vaginal and cervical Tissue than in Rectal Tissue. Although we do not know the concentrations of TFV-DP and FTC-TP required to prevent HIV infection, the differences in Tissue concentrations are substantial and suggest implications for HIV prevention. In the VOICE trial,3 the lack of protection with oral TDF could reflect low Tissue concentrations of the drug. How, then, can we explain the protection provided by TDF in PIP6? It seems possible that HIV transmission in a discordant couple relationship might be prevented differently, or more readily. It is also possible, indeed likely, that adherence in a discordant relationship is better, resulting in a critical (currently unknown) Tissue concentration being achieved. The protection from HIV observed with the TDF and FTC combination in TDF25 and PIP6 suggests an important role for higher FTC concentrations, perhaps in combination with the lower concentrations of tenofovir, in the female genital tract. The differences in benefit of 1% tenofovir gel in CAPRISA 0042 and VOICE3 demand further exploration; the studies used different dosage schedules, and women at different sites might differ in ways that affect study outcomes (table). Adherence, however, will still determine the value of antiretroviral agents both in clinical trials and in clinical practice. In HPTN 0521 HIV viraemia was prospectively monitored in infected trial participants to ensure adherence, which allowed determination of the antiretrovirals’ ability to suppress transmission under ideal conditions. To date, the only prospective measurement of adherence in pre-exposure prophylaxis trials has been by self-report or pill counts, which might overestimate adherence.13 These values have then been compared to potential efficacy with post-hoc measurement of blood concentrations in a limited number of samples using a case-control design. In the iPrEx trial,4 the investigators used combined data to argue that pre-exposure prophylaxis was perhaps more than 90% protective in participants who took the treatment reliably. In CAPRISA 004,2 the effectiveness of protection was 52% with more than 80% adherence as measured retrospectively by evaluation of used gel applicators. But such retrospective analyses cannot be used to confirm the intervention’s success or failure. Less adherence to daily use of 1% tenofovir gel in VOICE3 could have compromised benefit relative to the coitally-driven use of the gel in CAPRISA 004.2 Paradoxically, daily use may confer a degree of difficulty that reduces adherence. We believe that, before future pre-exposure prophylaxis studies are undertaken, knowledge of biological plausibility must be secure. Evidence of strong and durable Tissue concentrations of active agents should be a condition of such studies taking place. Powerful antiviral agents limited in their Tissue penetration, intracellular metabolism, or Tissue half-life are not appropriate for pre-exposure prophylaxis. Moreover, adherence must be measured prospectively in future trials.14,15 Under these conditions trial participants who do not adhere to treatment can be counselled or the study analysis designed to incorporate these most rigorous measures of adherence. To predict success in clinical practice reliably, both the drug concentrations needed for protective efficacy and the best way to assess adherence in clinical trials must first be defined. Effectiveness trials that depend on adherence and many other factors—the real world—should await proof that antiretroviral agents work as anticipated.
John Collinge - One of the best experts on this subject based on the ideXlab platform.
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Prion infectivity in variant Creutzfeldt-Jakob disease rectum
GUT, 2007Co-Authors: John CollingeAbstract:Background: Disease-related prion protein (PrPSc) is readily detectable in lymphoreticular Tissues in variant Creutzfeldt-Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic vCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrPSc: prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrPSc concentration typically reflects infectious prion titre.Aim: To investigate prion infectivity in vCJD Tissue containing barely detectable levels of PrPSc.Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M(+/+) Prnp(o/o))-35 and Tg(HuPrP129M(+/+) Prnp(o/o))-45 mice) were inoculated with brain or Rectal Tissue from a previously characterised patient with vCJD. These Tissues contain the maximum and minimum levels of detectable PrPSc that have been observed in vCJD.Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD Rectal Tissue containing PrPSc at a concentration of 10(4.7)-fold lower than that in vCJD brain.Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrPSc as a quantitative marker of prion infectivity in vCJD Tissues.
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prion infectivity in variant creutzfeldt jakob disease rectum commentary
Gut, 2007Co-Authors: M W Head, James W Ironside, Jonathan D F Wadsworth, Susan Joiner, Katie Fox, Jacqueline M Linehan, Melanie Desbruslais, S Brandner, Emmanuel A Asante, John CollingeAbstract:Background: Disease-related prion protein (PrP Sc ) is readily detectable in lymphoreticular Tissues in variant Creutzfeldt-Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic VCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrP Sc :prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrP Sc concentration typically reflects infectious prion titre. Aim: To investigate prion infectivity in vCJD Tissue containing barely detectable levels of PrP Sc . Methods: Transgenic mice expressing only human PrP (Tg(HuPrP129M +/+ Prnp°/°)-35 and Tg(HuPrP129M +/ + Prnp °/° )-45 mice) were inoculated with brain or Rectal Tissue from a previously characterised patient with vCJD. These Tissues contain the maximum and minimum levels of detectable PrP Sc that have been observed in vCJD. Results: Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD Rectal Tissue containing PrP Sc at a concentration of 10 4.7 -fold lower than that in vCJD brain. Conclusions: These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrP Sc as a quantitative marker of prion infectivity in vCJD Tissues.
Myron S Cohen - One of the best experts on this subject based on the ideXlab platform.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:BACKGROUND Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions. METHODS A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One Rectal Tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal Tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions.
-
pre exposure prophylaxis for hiv prevention how to predict success
The Lancet, 2012Co-Authors: Angela D M Kashuba, Kristine B Patterson, Julie B Dumond, Myron S CohenAbstract:Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052,1 showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 0042 and VOICE3), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX,4 TDF2,5 Partners in Prevention [PIP],6 and Fem-PrEP7), and two used oral TDF alone (VOICE3 and PIP6). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004,2 iPrEx,4 TDF2,5 and PIP6) and of futility (VOICE3 and Fem-PrEP7). Table Antiretroviral-based HIV prevention studies Clearly, results on pre-exposure prophylaxis will be used to inform policy and to plan future research, and so the trials’ findings need to be considered carefully. There were key differences in the pre-exposure prophylaxis trials (table): each included different populations with distinct routes of HIV transmission. For example, iPrEx4 was the first success for oral pre-exposure prophylaxis and focused on men who have sex with men. It is reasonable to assume that anal intercourse was the key route of transmission in the iPrEx trial,4 and was less frequently the source of HIV infection in the heterosexual women and men in the Fem-PrEP,7 VOICE,3 TDF2,5 and PIP6 studies. HIV acquisition is more efficient after anal intercourse,8 and more HIV variants are acquired during anal intercourse than cervicovaginal exposure.9 We have reported substantial differences in anti-retroviral drug concentrations in mucosal Tissues.10–12 After oral administration of co-formulated TDF and FTC, there were 100-fold higher concentrations of tenofovir in Rectal Tissue compared with cervicovaginal Tissue.12 Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine (FTC-TP) are required to inhibit HIV replication.12 100-fold higher concentrations of TFV-DP were detected in the rectum as compared with cervix and vagina.12 Conversely, FTC-TP concentrations were 10–15 fold higher in vaginal and cervical Tissue than in Rectal Tissue. Although we do not know the concentrations of TFV-DP and FTC-TP required to prevent HIV infection, the differences in Tissue concentrations are substantial and suggest implications for HIV prevention. In the VOICE trial,3 the lack of protection with oral TDF could reflect low Tissue concentrations of the drug. How, then, can we explain the protection provided by TDF in PIP6? It seems possible that HIV transmission in a discordant couple relationship might be prevented differently, or more readily. It is also possible, indeed likely, that adherence in a discordant relationship is better, resulting in a critical (currently unknown) Tissue concentration being achieved. The protection from HIV observed with the TDF and FTC combination in TDF25 and PIP6 suggests an important role for higher FTC concentrations, perhaps in combination with the lower concentrations of tenofovir, in the female genital tract. The differences in benefit of 1% tenofovir gel in CAPRISA 0042 and VOICE3 demand further exploration; the studies used different dosage schedules, and women at different sites might differ in ways that affect study outcomes (table). Adherence, however, will still determine the value of antiretroviral agents both in clinical trials and in clinical practice. In HPTN 0521 HIV viraemia was prospectively monitored in infected trial participants to ensure adherence, which allowed determination of the antiretrovirals’ ability to suppress transmission under ideal conditions. To date, the only prospective measurement of adherence in pre-exposure prophylaxis trials has been by self-report or pill counts, which might overestimate adherence.13 These values have then been compared to potential efficacy with post-hoc measurement of blood concentrations in a limited number of samples using a case-control design. In the iPrEx trial,4 the investigators used combined data to argue that pre-exposure prophylaxis was perhaps more than 90% protective in participants who took the treatment reliably. In CAPRISA 004,2 the effectiveness of protection was 52% with more than 80% adherence as measured retrospectively by evaluation of used gel applicators. But such retrospective analyses cannot be used to confirm the intervention’s success or failure. Less adherence to daily use of 1% tenofovir gel in VOICE3 could have compromised benefit relative to the coitally-driven use of the gel in CAPRISA 004.2 Paradoxically, daily use may confer a degree of difficulty that reduces adherence. We believe that, before future pre-exposure prophylaxis studies are undertaken, knowledge of biological plausibility must be secure. Evidence of strong and durable Tissue concentrations of active agents should be a condition of such studies taking place. Powerful antiviral agents limited in their Tissue penetration, intracellular metabolism, or Tissue half-life are not appropriate for pre-exposure prophylaxis. Moreover, adherence must be measured prospectively in future trials.14,15 Under these conditions trial participants who do not adhere to treatment can be counselled or the study analysis designed to incorporate these most rigorous measures of adherence. To predict success in clinical practice reliably, both the drug concentrations needed for protective efficacy and the best way to assess adherence in clinical trials must first be defined. Effectiveness trials that depend on adherence and many other factors—the real world—should await proof that antiretroviral agents work as anticipated.
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penetration of tenofovir and emtricitabine in mucosal Tissues implications for prevention of hiv 1 transmission
Science Translational Medicine, 2011Co-Authors: Kristine B Patterson, Myron S Cohen, Nicholas J Shaheen, Heather M A Prince, Eric Kraft, Amanda J Jenkins, James F Rooney, Angela D M KashubaAbstract:A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and coloRectal mucosal Tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from Rectal, vaginal, and cervical Tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC1–14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC1–14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In Rectal Tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical Tissues. Vaginal and cervical Tissue concentrations of FTC were 10- to 15-fold higher than in Rectal Tissue. Despite high concentrations of FTC in vaginal and cervical Tissue, FTC-TP concentrations in all Tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal Tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.
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single and multiple dose pharmacokinetics of maraviroc in saliva semen and Rectal Tissue of healthy hiv negative men
The Journal of Infectious Diseases, 2011Co-Authors: Kevin C Brown, Kristine B Patterson, Julie B Dumond, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Paris Heidt, Angela D M KashubaAbstract:Between 2004 and 2007, the incidence of HIV/AIDS increased 15% in the United States [1]. In men who have sex with men (MSM), this increase was 26%. The highest risk of HIV acquisition occurs with receptive anal intercourse [2], as the Rectal mucosa is rich in lymphoid Tissue and has a thin epithelium [3]. Data from the Phase III CAPRISA 004 study, which evaluated a topical tenofovir gel formulation for prevention of HIV acquisition in women, not only provide the proof of concept for microbicides but also further evidence that antiretroviral-based prevention strategies can be effective [4]. To date, topical Rectal microbicide and vaccine trials have not demonstrated compelling benefit in HIV prevention; therefore, investigations using orally administered antiretrovirals are still necessary [5, 6]. Antiretrovirals can be used for both primary and secondary HIV prevention. Primary prophylaxis prevents acquisition of HIV in an uninfected individual, and secondary prophylaxis reduces the likelihood of an HIV-infected individual transmitting HIV. Primary prevention can be further separated into pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). PrEP requires administering antiretrovirals to at-risk individuals prior to a potential HIV exposure, and PEP involves administering antiretrovirals to an HIV-negative individual after a suspected exposure to HIV. Measuring antiretroviral exposure in Rectal Tissue could assist in selecting drugs and dosing regimens for PrEP and PEP. HIV transmission modeling has correlated increasing concentrations of HIV RNA in semen to an increasing probability of infection [7]. Despite suppression of HIV RNA in blood, HIV RNA can still be detected in genital secretions of up to 8% of HIV-infected men on antiretroviral therapy [8]. Using selected antiretrovirals to target the genital tract and decrease HIV replication in genital secretions has implications for transmission. If semen drug concentrations are high enough, it might be also be possible to deliver a protective amount of drug to a receptive mucosal surface through this route [9]. The ability to monitor drug concentrations has allowed clinicians to make important decisions regarding adherence to antiretroviral regimens. Under most conditions, concentration monitoring requires a blood sample. Saliva sampling has been explored as an alternative to blood sampling and has the advantages of being less invasive and requiring less processing time upon collection [10]. Within the female genital tract, the CCR5 antagonist maraviroc (Celsentri/Selzentry; Pfizer, Inc) achieves very high exposure [11]. The current study was designed to understand exposure of maraviroc in the saliva, seminal fluid, and Rectal Tissue following single and multiple doses.
Kristine B Patterson - One of the best experts on this subject based on the ideXlab platform.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:BACKGROUND Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions. METHODS A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One Rectal Tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal Tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions.
-
pre exposure prophylaxis for hiv prevention how to predict success
The Lancet, 2012Co-Authors: Angela D M Kashuba, Kristine B Patterson, Julie B Dumond, Myron S CohenAbstract:Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052,1 showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 0042 and VOICE3), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX,4 TDF2,5 Partners in Prevention [PIP],6 and Fem-PrEP7), and two used oral TDF alone (VOICE3 and PIP6). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004,2 iPrEx,4 TDF2,5 and PIP6) and of futility (VOICE3 and Fem-PrEP7). Table Antiretroviral-based HIV prevention studies Clearly, results on pre-exposure prophylaxis will be used to inform policy and to plan future research, and so the trials’ findings need to be considered carefully. There were key differences in the pre-exposure prophylaxis trials (table): each included different populations with distinct routes of HIV transmission. For example, iPrEx4 was the first success for oral pre-exposure prophylaxis and focused on men who have sex with men. It is reasonable to assume that anal intercourse was the key route of transmission in the iPrEx trial,4 and was less frequently the source of HIV infection in the heterosexual women and men in the Fem-PrEP,7 VOICE,3 TDF2,5 and PIP6 studies. HIV acquisition is more efficient after anal intercourse,8 and more HIV variants are acquired during anal intercourse than cervicovaginal exposure.9 We have reported substantial differences in anti-retroviral drug concentrations in mucosal Tissues.10–12 After oral administration of co-formulated TDF and FTC, there were 100-fold higher concentrations of tenofovir in Rectal Tissue compared with cervicovaginal Tissue.12 Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine (FTC-TP) are required to inhibit HIV replication.12 100-fold higher concentrations of TFV-DP were detected in the rectum as compared with cervix and vagina.12 Conversely, FTC-TP concentrations were 10–15 fold higher in vaginal and cervical Tissue than in Rectal Tissue. Although we do not know the concentrations of TFV-DP and FTC-TP required to prevent HIV infection, the differences in Tissue concentrations are substantial and suggest implications for HIV prevention. In the VOICE trial,3 the lack of protection with oral TDF could reflect low Tissue concentrations of the drug. How, then, can we explain the protection provided by TDF in PIP6? It seems possible that HIV transmission in a discordant couple relationship might be prevented differently, or more readily. It is also possible, indeed likely, that adherence in a discordant relationship is better, resulting in a critical (currently unknown) Tissue concentration being achieved. The protection from HIV observed with the TDF and FTC combination in TDF25 and PIP6 suggests an important role for higher FTC concentrations, perhaps in combination with the lower concentrations of tenofovir, in the female genital tract. The differences in benefit of 1% tenofovir gel in CAPRISA 0042 and VOICE3 demand further exploration; the studies used different dosage schedules, and women at different sites might differ in ways that affect study outcomes (table). Adherence, however, will still determine the value of antiretroviral agents both in clinical trials and in clinical practice. In HPTN 0521 HIV viraemia was prospectively monitored in infected trial participants to ensure adherence, which allowed determination of the antiretrovirals’ ability to suppress transmission under ideal conditions. To date, the only prospective measurement of adherence in pre-exposure prophylaxis trials has been by self-report or pill counts, which might overestimate adherence.13 These values have then been compared to potential efficacy with post-hoc measurement of blood concentrations in a limited number of samples using a case-control design. In the iPrEx trial,4 the investigators used combined data to argue that pre-exposure prophylaxis was perhaps more than 90% protective in participants who took the treatment reliably. In CAPRISA 004,2 the effectiveness of protection was 52% with more than 80% adherence as measured retrospectively by evaluation of used gel applicators. But such retrospective analyses cannot be used to confirm the intervention’s success or failure. Less adherence to daily use of 1% tenofovir gel in VOICE3 could have compromised benefit relative to the coitally-driven use of the gel in CAPRISA 004.2 Paradoxically, daily use may confer a degree of difficulty that reduces adherence. We believe that, before future pre-exposure prophylaxis studies are undertaken, knowledge of biological plausibility must be secure. Evidence of strong and durable Tissue concentrations of active agents should be a condition of such studies taking place. Powerful antiviral agents limited in their Tissue penetration, intracellular metabolism, or Tissue half-life are not appropriate for pre-exposure prophylaxis. Moreover, adherence must be measured prospectively in future trials.14,15 Under these conditions trial participants who do not adhere to treatment can be counselled or the study analysis designed to incorporate these most rigorous measures of adherence. To predict success in clinical practice reliably, both the drug concentrations needed for protective efficacy and the best way to assess adherence in clinical trials must first be defined. Effectiveness trials that depend on adherence and many other factors—the real world—should await proof that antiretroviral agents work as anticipated.
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penetration of tenofovir and emtricitabine in mucosal Tissues implications for prevention of hiv 1 transmission
Science Translational Medicine, 2011Co-Authors: Kristine B Patterson, Myron S Cohen, Nicholas J Shaheen, Heather M A Prince, Eric Kraft, Amanda J Jenkins, James F Rooney, Angela D M KashubaAbstract:A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and coloRectal mucosal Tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from Rectal, vaginal, and cervical Tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC1–14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC1–14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In Rectal Tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical Tissues. Vaginal and cervical Tissue concentrations of FTC were 10- to 15-fold higher than in Rectal Tissue. Despite high concentrations of FTC in vaginal and cervical Tissue, FTC-TP concentrations in all Tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal Tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.
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single and multiple dose pharmacokinetics of maraviroc in saliva semen and Rectal Tissue of healthy hiv negative men
The Journal of Infectious Diseases, 2011Co-Authors: Kevin C Brown, Kristine B Patterson, Julie B Dumond, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Paris Heidt, Angela D M KashubaAbstract:Between 2004 and 2007, the incidence of HIV/AIDS increased 15% in the United States [1]. In men who have sex with men (MSM), this increase was 26%. The highest risk of HIV acquisition occurs with receptive anal intercourse [2], as the Rectal mucosa is rich in lymphoid Tissue and has a thin epithelium [3]. Data from the Phase III CAPRISA 004 study, which evaluated a topical tenofovir gel formulation for prevention of HIV acquisition in women, not only provide the proof of concept for microbicides but also further evidence that antiretroviral-based prevention strategies can be effective [4]. To date, topical Rectal microbicide and vaccine trials have not demonstrated compelling benefit in HIV prevention; therefore, investigations using orally administered antiretrovirals are still necessary [5, 6]. Antiretrovirals can be used for both primary and secondary HIV prevention. Primary prophylaxis prevents acquisition of HIV in an uninfected individual, and secondary prophylaxis reduces the likelihood of an HIV-infected individual transmitting HIV. Primary prevention can be further separated into pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). PrEP requires administering antiretrovirals to at-risk individuals prior to a potential HIV exposure, and PEP involves administering antiretrovirals to an HIV-negative individual after a suspected exposure to HIV. Measuring antiretroviral exposure in Rectal Tissue could assist in selecting drugs and dosing regimens for PrEP and PEP. HIV transmission modeling has correlated increasing concentrations of HIV RNA in semen to an increasing probability of infection [7]. Despite suppression of HIV RNA in blood, HIV RNA can still be detected in genital secretions of up to 8% of HIV-infected men on antiretroviral therapy [8]. Using selected antiretrovirals to target the genital tract and decrease HIV replication in genital secretions has implications for transmission. If semen drug concentrations are high enough, it might be also be possible to deliver a protective amount of drug to a receptive mucosal surface through this route [9]. The ability to monitor drug concentrations has allowed clinicians to make important decisions regarding adherence to antiretroviral regimens. Under most conditions, concentration monitoring requires a blood sample. Saliva sampling has been explored as an alternative to blood sampling and has the advantages of being less invasive and requiring less processing time upon collection [10]. Within the female genital tract, the CCR5 antagonist maraviroc (Celsentri/Selzentry; Pfizer, Inc) achieves very high exposure [11]. The current study was designed to understand exposure of maraviroc in the saliva, seminal fluid, and Rectal Tissue following single and multiple doses.
Heather M A Prince - One of the best experts on this subject based on the ideXlab platform.
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cervicovaginal and Rectal fluid as a surrogate marker of antiretroviral Tissue concentration implications for clinical trial design
Journal of Acquired Immune Deficiency Syndromes, 2016Co-Authors: Mackenzie L Cottrell, Stephanie Malone, Heather M A Prince, Andrew G Allmon, Katie R Mollan, Michael G Hudgens, Craig Sykes, Nicole White, Evan S Dellon, Ryan D MadanickAbstract:BACKGROUND Quantifying Tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (Rectal fluid; RF) might be used as Tissue concentration surrogates, but these relationships are not well characterized. METHODS Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and Rectal Tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. RESULTS CVF exposure increased linearly with dose for all antiretrovirals (r(2) ≥ 0.23, P ≤ 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal Tissue concentrations (female genital tract r(2) ≥ 0.37, Rectal Tissue (2)r ≥ 0.50, P ≤ 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) ≥ 0.81, P < 0.001). The same was noted for Rectal Tissue (r(2) ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of Tissue concentration (r(2) = 0.91, P < 0.001). CONCLUSIONS Mucosal fluids were positively correlated with Tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract Tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of Tissue concentrations for these antiretrovirals.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:BACKGROUND Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions. METHODS A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One Rectal Tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal Tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.
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single and multiple dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and Rectal Tissue of hiv negative men
Journal of Acquired Immune Deficiency Syndromes, 2012Co-Authors: Kevin C Brown, Kristine B Patterson, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Steven Jennings, Angela D M KashubaAbstract:Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal Tissues is paramount to designing future prevention interventions.
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penetration of tenofovir and emtricitabine in mucosal Tissues implications for prevention of hiv 1 transmission
Science Translational Medicine, 2011Co-Authors: Kristine B Patterson, Myron S Cohen, Nicholas J Shaheen, Heather M A Prince, Eric Kraft, Amanda J Jenkins, James F Rooney, Angela D M KashubaAbstract:A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and coloRectal mucosal Tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from Rectal, vaginal, and cervical Tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC1–14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC1–14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In Rectal Tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical Tissues. Vaginal and cervical Tissue concentrations of FTC were 10- to 15-fold higher than in Rectal Tissue. Despite high concentrations of FTC in vaginal and cervical Tissue, FTC-TP concentrations in all Tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal Tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.
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single and multiple dose pharmacokinetics of maraviroc in saliva semen and Rectal Tissue of healthy hiv negative men
The Journal of Infectious Diseases, 2011Co-Authors: Kevin C Brown, Kristine B Patterson, Julie B Dumond, Myron S Cohen, Stephanie Malone, Nicholas J Shaheen, Heather M A Prince, Melissa Spacek, Paris Heidt, Angela D M KashubaAbstract:Between 2004 and 2007, the incidence of HIV/AIDS increased 15% in the United States [1]. In men who have sex with men (MSM), this increase was 26%. The highest risk of HIV acquisition occurs with receptive anal intercourse [2], as the Rectal mucosa is rich in lymphoid Tissue and has a thin epithelium [3]. Data from the Phase III CAPRISA 004 study, which evaluated a topical tenofovir gel formulation for prevention of HIV acquisition in women, not only provide the proof of concept for microbicides but also further evidence that antiretroviral-based prevention strategies can be effective [4]. To date, topical Rectal microbicide and vaccine trials have not demonstrated compelling benefit in HIV prevention; therefore, investigations using orally administered antiretrovirals are still necessary [5, 6]. Antiretrovirals can be used for both primary and secondary HIV prevention. Primary prophylaxis prevents acquisition of HIV in an uninfected individual, and secondary prophylaxis reduces the likelihood of an HIV-infected individual transmitting HIV. Primary prevention can be further separated into pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). PrEP requires administering antiretrovirals to at-risk individuals prior to a potential HIV exposure, and PEP involves administering antiretrovirals to an HIV-negative individual after a suspected exposure to HIV. Measuring antiretroviral exposure in Rectal Tissue could assist in selecting drugs and dosing regimens for PrEP and PEP. HIV transmission modeling has correlated increasing concentrations of HIV RNA in semen to an increasing probability of infection [7]. Despite suppression of HIV RNA in blood, HIV RNA can still be detected in genital secretions of up to 8% of HIV-infected men on antiretroviral therapy [8]. Using selected antiretrovirals to target the genital tract and decrease HIV replication in genital secretions has implications for transmission. If semen drug concentrations are high enough, it might be also be possible to deliver a protective amount of drug to a receptive mucosal surface through this route [9]. The ability to monitor drug concentrations has allowed clinicians to make important decisions regarding adherence to antiretroviral regimens. Under most conditions, concentration monitoring requires a blood sample. Saliva sampling has been explored as an alternative to blood sampling and has the advantages of being less invasive and requiring less processing time upon collection [10]. Within the female genital tract, the CCR5 antagonist maraviroc (Celsentri/Selzentry; Pfizer, Inc) achieves very high exposure [11]. The current study was designed to understand exposure of maraviroc in the saliva, seminal fluid, and Rectal Tissue following single and multiple doses.