The Male Genital Tract Is Not a Pharmacological Sanctuary From Efavirenz

Avery, L. B.; Bakshi, Rahul P.; Cao, Ye; Cw, Hendrix

doi:10.1038/clpt.2011.99

Cited by 24 publications

(41 citation statements)

References 19 publications

(44 reference statements)

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“…Separation of the protein free from the protein bound was performed according to a method previously described elsewhere (Avery et al, 2011). Briefly, ultrafiltration of samples was performed using 96-well plates with a 10-kDa filter membrane (Millipore, Billerica, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Total concentrations of EFV were previously established in the paired blood plasma and seminal plasma samples with median (interquartile range [IQR]) concentrations of 2360 ng/ml (1530-4120) and 95 ng/ml (70-206), respectively (Avery et al, 2011). Total concentrations of EFV were previously measured in the paired blood plasma and cerebrospinal fluid samples with median (IQR) concentrations of 2170 ng/ml (1896-2520) and 19 ng/ml (7-24) (Tovar-Y-Romo et al, 2012).…”

Section: Quantitation Of Efv Metabolite Concentrations In Bloodmentioning

confidence: 99%

“…To measure the protein-free concentrations of the EFV metabolites, an established ultrafiltration method (Avery et al, 2011) was used. Protein-free concentrations of EFV metabolites were only detectable in seminal plasma with median (IQR) concentrations of 10.16 ng/ml (7.29-42.36) for 8-OH EFV, 6.55 ng/ml (5.14-22.18) for 7-OH EFV, and 4.04 ng/ml (3.98-5.80) for 8,14-OH EFV (Fig.…”

Section: Quantitation Of Efv Metabolite Concentrations In Bloodmentioning

confidence: 99%

“…Recent reports have revealed that there exists a 150-fold total concentration gradient for EFV from blood plasma to cerebrospinal fluid (Best et al, 2011) and 20-fold from blood plasma to seminal plasma (Avery et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…HIV-associated neurologic disease is relatively common, resulting in significant cognitive and neurologic impairment, but the etiology is incompletely understood (Resnick et al, 1988;Sacktor, 2002;McArthur, 2004;Valcour et al, 2012). The male genital tract has also shown poor ARV penetration (Kashuba et al, 1999;Avery et al, 2011) and is a compartment of concern in that it is the primary site of transmission through HIV-laden semen (Resnick et al, 1988;Stekler et al, 2008;UNAIDS, 2009). Although the ability of ARVs to penetrate these compartments is an important aspect of HIV therapy, in many cases a comprehensive understanding of the distribution of these drugs beyond the blood is lacking.…”

Section: Introductionmentioning

confidence: 99%

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Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

et al. 2012

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Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure.

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Section: Methodsmentioning

confidence: 99%

Section: Quantitation Of Efv Metabolite Concentrations In Bloodmentioning

confidence: 99%

Section: Quantitation Of Efv Metabolite Concentrations In Bloodmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

et al. 2012

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Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

Trezza

Kashuba

2014

Clin Pharmacokinet

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The incidence of HIV remains alarmingly high in many parts of the world. Prophylactic use of antiretrovirals, capable of concentrating in the anatomical sites of transmission, may reduce the risk of infection after an unprotected sexual exposure. To date, orally and topically administered antiretrovirals have exhibited variable success in preventing HIV transmission in large-scale clinical trials. Antiretroviral mucosal pharmacokinetics may help explain the outcomes of these investigations. Penetration and accumulation of antiretrovirals into sites of transmission can influence dosing strategies and pre-exposure prophylaxis clinical trial design. Antiretroviral tissue distribution varies widely within and between drug classes, attributed in part to their physicochemical properties and tissue-specific drug transporter expression. Nucleoside (-tide) reverse transcriptase inhibitors, the CCR5 antagonist maraviroc, and the integrase inhibitor raltegravir demonstrate the highest penetration into the male and female reproductive tracts and colorectal tissue relative to blood. This review will describe antiretroviral exposure in anatomic sites of transmission, and place these findings in context with the prevention of HIV and the efficacy of pre-exposure prophylactic strategies.

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A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women

Schalkwijk

Heine²,

Colbers³

et al. 2018

Clin Pharmacokinet

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BackgroundReducing the dose of efavirenz can improve safety, reduce costs, and increase access for patients with HIV infection. According to the World Health Organization, a similar dosing strategy for all patient populations is desirable for universal roll-out; however, it remains unknown whether the 400 mg daily dose is adequate during pregnancy.MethodsWe developed a mechanistic population pharmacokinetic model using pooled data from women included in seven studies (1968 samples, 774 collected during pregnancy). Total and free efavirenz exposure (AUC24 and C12) were predicted for 400 (reduced) and 600 mg (standard) doses in both pregnant and non-pregnant women.ResultsUsing a 400 mg dose, the median efavirenz total AUC24 and C12 during the third trimester of pregnancy were 91 and 87% of values among non-pregnant women, respectively. Furthermore, the median free efavirenz C12 and AUC24 were predicted to increase during pregnancy by 11 and 15%, respectively.ConclusionsIt was predicted that reduced-dose efavirenz provides adequate exposure during pregnancy. These findings warrant prospective confirmation.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0642-9) contains supplementary material, which is available to authorized users.

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The Male Genital Tract Is Not a Pharmacological Sanctuary From Efavirenz

Cited by 24 publications

References 19 publications

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women

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