Semen Quality and Drug Concentrations in Seminal Plasma of Patients Using a Didanosine or Didanosine Plus Tenofovir Containing Antiretroviral Regimen

Lowe, Selwyn H.; Leeuwen, Elisabeth van; Droste, Jacqueline A. H.; Veen, Fulco van der; Reiss, Peter; Lange, Joep M. A.; Burger, David M.; Repping, Sjoerd; Prins, Jan M.

doi:10.1097/ftd.0b013e31811fef29

Cited by 22 publications

(17 citation statements)

References 18 publications

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“…The discrepancy between the median C 24 values probably results from the steady-state condition and an accumulation of TFV in the male genital tract with repeated administrations. Other studies have reported higher TFV concentrations in SP, with SP-to-BP concentration ratios of 2.8 and 3.3 (13,14). The mean C 24 ratio at steady state was reported to be 5.1 (15), close to the mean C 24 ratio at steady state of 6.6 estimated in our study.…”

Section: Discussionsupporting

confidence: 75%

“…Available data on tenofovir (TFV) SP concentrations are sparse, although this drug is recommended as a preferred choice in first-line regimens for HIV treatment and postexposure prophylaxis and a large body of evidence from trials using TFV-based regimens now supports the concepts of "treatment as prevention" and "preexposure prophylaxis" (11,12). Four studies have suggested an accumulation of TFV in the male genital tract to different extents (13)(14)(15)(16). Mean TFV SP-to-BP concentrations ratios have been estimated at 2.8 (n ϭ 4 men) and 3.3 (n ϭ 15 men) for various sampling times (13,14).…”

mentioning

confidence: 99%

“…Four studies have suggested an accumulation of TFV in the male genital tract to different extents (13)(14)(15)(16). Mean TFV SP-to-BP concentrations ratios have been estimated at 2.8 (n ϭ 4 men) and 3.3 (n ϭ 15 men) for various sampling times (13,14). Mean TFV SP-to-BP concentration ratios at 24 h (C 24 ) were estimated at 4.4 for a single dose and 5.1 at steady state (n ϭ 9 men) (15).…”

mentioning

confidence: 99%

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Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Valade

Bouazza

Lui

et al. 2017

Antimicrob Agents Chemother

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The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ]) were higher in SP than in BP (median AUC 0 -24 , 7.01 versus 2.97 mg · liter Ϫ1 · h, respectively). The median (range) SP-to-BP AUC 0 -24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0 -24 or TFV SP-to-BP AUC 0 -24 ratio on spVL was not significant (P ϭ 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

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confidence: 99%

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Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Valade

Bouazza

Lui

et al. 2017

Antimicrob Agents Chemother

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“…Clinical data have shown seminal plasma concentrations of zidovudine (AZT, 39-azido-39-deoxythymidine) and didanosine (ddI, 29,39-dideoxyinosine) are up to 10-fold higher than blood plasma (Lowe et al, 2007;Dumond et al, 2008). Understanding the transepithelial transport pathway NRTIs use to bypass the BTB could potentially be useful in designing other drugs to cross into the lumen of seminiferous tubules.…”

Section: Introductionmentioning

confidence: 99%

Basolateral Uptake of Nucleosides by Sertoli Cells Is Mediated Primarily by Equilibrative Nucleoside Transporter 1

Klein

Evans

Hardwick

et al. 2013

J Pharmacol Exp Ther

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The blood-testis barrier (BTB) prevents the entry of many xenobiotic compounds into seminiferous tubules thereby protecting developing germ cells. Understanding drug transport across the BTB may improve drug delivery into the testis. Members of one class of drug, nucleoside reverse transcriptase inhibitors (NRTIs), do penetrate the BTB, presumably through interaction with physiologic nucleoside transporters. By investigating the mechanism of nucleoside transport, it may be possible to design other drugs to bypass the BTB in a similar manner. We present a novel ex vivo technique to study transport at the BTB that employs isolated, intact seminiferous tubules. Using this system, we found that over 80% of total uptake by seminiferous tubules of the model nucleoside uridine could be inhibited by 100 nM nitrobenzylmercaptopurine riboside (NBMPR, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine), a concentration that selectively inhibits equilibrative nucleoside transporter 1 (ENT1) activity. In primary cultured rat Sertoli cells, 100 nM NBMPR inhibited all transepithelial transport and basolateral uptake of uridine. Immunohistochemical staining showed ENT1 to be located on the basolateral membrane of human and rat Sertoli cells, whereas ENT2 was located on the apical membrane of Sertoli cells. Transepithelial transport of uridine by rat Sertoli cells was partially inhibited by the NRTIs zidovudine, didanosine, and tenofovir disoproxil fumarate, consistent with an interaction between these drugs and ENT transporters. These data indicate that ENT1 is the primary route for basolateral nucleoside uptake into Sertoli cells and a possible mechanism for nucleosides and nucleoside-based drugs to undergo transepithelial transport.

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“…The model developed for 3TC could be applied to FTC disposition in the male genital tract, if such data were available. The penetration of TDF into SP has been studied by several groups (25,26), but only one paper has examined its active diphosphate form in SMCs (27). Vourvahis and colleagues found 9-fold-higher concentrations of the diphosphate in SMCs at a first dose of TDF monotherapy, and 17-fold-higher concentrations in SMCs at steady state; in SMCs, these concentrations exceed the proposed IC 90 in PBMCs (16 fmol/10 6 cells) (28) by at least 10-fold.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells

Dumond¹,

Yang²,

Kendrick³

et al. 2015

Antimicrob Agents Chemother

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The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/ PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC 50 ) (as established for PBMCs, assuming SMC IC 50 ‫؍‬ PBMC IC 50 ) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.O ngoing viral replication in the male genital tract poses challenges for HIV prevention, treatment, and cure. From a prevention standpoint, virus in semen remains a major vector of HIV transmission; in serodiscordant heterosexual couples, early initiation of antiretroviral (ARV) treatment in the infected partner, with maintained suppression of peripheral HIV RNA, can reduce the rate of transmission by 96%, compared to delaying ARV treatment until later in the course of disease (1). The single linked HIV transmission event in the HPTN052 early treatment arm was from an infected male to his uninfected female partner within approximately 29 days of starting ARV therapy (1, 2). Additionally, to date, evidence strongly suggests that early, effective antiretroviral treatment limits the size of the viral reservoir, providing the best chance of HIV eradication (3). Finally, ongoing viral replication has been demonstrated in sanctuary sites, such as the central nervous system, gut-associated lymphoid tissue, and the genital tract, where antiretroviral concentrations may differ from those seen systemically (reviewed in reference 4). Since HIV eradication will not be possible with ongoing viral replication in sanctuary compartments, it is important to select ARVs with optimized pharmacokinetic (PK) and pharmacodynamic profiles to...

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Semen Quality and Drug Concentrations in Seminal Plasma of Patients Using a Didanosine or Didanosine Plus Tenofovir Containing Antiretroviral Regimen

Cited by 22 publications

References 18 publications

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Basolateral Uptake of Nucleosides by Sertoli Cells Is Mediated Primarily by Equilibrative Nucleoside Transporter 1

Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells

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