Antiretroviral drug concentrations in semen of HIV-1 infected men

Taylor, Stephen; Pereira, Arlene S.

doi:10.1136/sti.77.1.4

Cited by 71 publications

(57 citation statements)

References 49 publications

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“…Although it is not a common practice to collect semen in human ADME studies, detection of drugs and their metabolites in semen has been reported previously, particularly in patients with HIV (Ette et al, 1988; Taylor and Pereira, 2001;Avery et al, 2013). Semen was evaluated since subjects in prior studies had reported semen discoloration after taking KAE609 at higher doses.…”

Section: Discussionmentioning

confidence: 99%

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

Huskey¹,

Zhu²,

Fredenhagen³

et al. 2016

Drug Metabolism and Disposition

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KAE609 [(19R,39S)-5,79-dichloro-69-fluoro-39-methyl-29,39,49,99-tetrahydrospiro[indoline-3,19-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [ 14 C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta.

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Section: Discussionmentioning

confidence: 99%

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

Huskey¹,

Zhu²,

Fredenhagen³

et al. 2016

Drug Metabolism and Disposition

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“…Furthermore, the detection of HIV-1 RNA in the semen of highly active anti-retroviral therapy-treated seropositive men, even in the absence of detectable levels of viral RNA in plasma, indicates that the male reproductive tract may constitute a sanctuary for HIV-1 replication. 4 -9 Indeed, subtherapeutic concentrations of protease inhibitors are evidenced in semen, 10 and sexual transmission of drug-resistant strains are currently on the rise. [11][12][13] Few previous studies have sought the presence of HIV in testes from acquired immune deficiency syndrome (AIDS)-deceased men, and what data there are remain controversial, 1 whereas, for obvious ethical reasons, in-depth investigations of the impact of HIV on the testis of asymptomatic men have never been performed.…”

mentioning

confidence: 99%

Susceptibility of Human Testis to Human Immunodeficiency Virus-1 Infection in Situ and in Vitro

Roulet

Satie

Ruffault

et al. 2006

The American Journal of Pathology

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Semen represents the main vector for human immunodeficiency virus (HIV) dissemination worldwide and has been shown to harbor replication-competent virus despite otherwise effective highly active anti-retroviral therapy, which achieves undetectable viral load in plasma. Despite this, the origin of seminal HIV particles remains unclear, as does the question of whether the male genital tract organs contribute virus to semen. Here we investigated the presence of HIV receptors within the human testis using immunohistochemistry and quantitative real-time polymerase chain reaction. We also analyzed the infectivity of a dual tropic HIV-1 strain in an organotypic culture, as well as the impact of viral exposure on testosterone production. Our study establishes that CXCR4 ؉ , CCR5 ؉ , CD4 ؉ , and DC-SIGN With sexual contact being the main cause of the spread of human immunodeficiency virus (HIV) and male to female transmission rates being higher and more efficient than female to male, semen represents the foremost vector of HIV dissemination worldwide. However, the origin of the virus in the semen is still unclear. Several arguments point to the existence of local sources producing free viral particles in this bodily fluid. First, a number of studies clearly indicate that semen represents a viral compartment distinct from the blood.

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“…[8,9]. Außerdem ist zu bedenken, dass nicht alle antiretroviralen Medikamente in den Genitalflüssigkeiten dieselben therapeutisch wirksamen Konzentrationen erreichen wie im Plasma und dass es daher im genitalen Viruskompartiment zu einer Resistenzbildung kommen kann, die sich zunächst in Blutuntersuchungen nicht widerspiegelt [10,11]. Schließlich ist auch noch zu berücksichtigen, dass es bei inkonsequenter Einnahme der Medikamente zu einer phasenhaften Virusreplikation und schließlich ebenfalls zu einer Resistenzentwicklung kommen kann [12].…”

Section: Introductionunclassified

Risiken und Wege der HIV-Übertragung

Marcus¹

2000

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschu

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Antiretroviral drug concentrations in semen of HIV-1 infected men

Cited by 71 publications

References 49 publications

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

Susceptibility of Human Testis to Human Immunodeficiency Virus-1 Infection in Situ and in Vitro

Risiken und Wege der HIV-Übertragung

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