Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs

Anderson, Peter L.

doi:10.1097/coh.0b013e3282f85dc1

Cited by 8 publications

(6 citation statements)

References 50 publications

(28 reference statements)

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“…However, these kinds of in vitro findings do not reliably translate to clinical relevance. 31 Further studies in vivo are needed to explore hormone effects on intracellular TFV-DP and FTC-TP including transporter expression in tissues of relevance for HIV infection. Given the difficulty in studying these issues in vivo, this is a well-suited setting for simulations and physiologically based pharmacokinetic modeling.…”

Section: Pharmacology Of Tdf–ftc For Prepmentioning

confidence: 99%

Pharmacologic Considerations for Preexposure Prophylaxis in Transgender Women

Anderson

Reirden

Castillo‐Mancilla

2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Studies of tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC)-based pre-exposure prophylaxis (PrEP) have not focused on transgendered women, who are at disproportionate risk of HIV acquisition. Concerns exist for drug interactions between cross-sex therapy (estradiol, progestins, and spironolactone) with TDF-FTC. This review assessed the experimental and theoretical risk for such drug interactions. It was found that none of these medications are implicated as major perpetrators of drug interactions, and the classes utilize different metabolic pathways for clearance, suggesting a low likelihood for interactions in either direction. Subanalyses of transgender women in iPrEx suggested PrEP efficacy if adherence was high. Nevertheless, several research gaps were identified, particularly the need for controlled interaction studies in transgendered women, including effects on renal clearance, intracellular tenofovir-diphosphate and emtricitabine-triphosphate in target cells, as well as hormone effects on HIV susceptibility and innate immunity. PrEP should continue to be offered to transgender women while additional research is planned or pending.

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Section: Pharmacology Of Tdf–ftc For Prepmentioning

confidence: 99%

Pharmacologic Considerations for Preexposure Prophylaxis in Transgender Women

Anderson

Reirden

Castillo‐Mancilla

2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Nucleoside analogs are widely used for the prevention and treatment of several viral infections, including human immunodeficiency virus, hepatitis B virus, and herpes infections ( Albrecht et al, 1970 ; Burchenal et al, 1975 ; Aguirrebengoa et al, 1996 ; Adams et al, 1997 ; Bavoux et al, 2000 ; Quan and Peters, 2004 ; Anderson, 2008 ; Angusti et al, 2008 ; Ambrose et al, 2009 ; Billioud et al, 2011 ; Agarwal et al, 2015 ; Cao et al, 2015 ; Ehteshami et al, 2017 ). Due to their hydrophilic nature, nucleoside analogs depend on a carrier-mediated transport process to permeate through host cell membranes before exhibiting their antiviral activities ( Yao et al, 1996 ; Damaraju et al, 2011 ; Moss et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Structural and Molecular Features Involved in the Transport of 3′-Deoxy-Nucleoside Analogs by Human Equilibrative Nucleoside Transporter 3

2018

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Combination antiretroviral drug treatments depend on 3′-deoxy-nucleoside analogs such as 3′-azido-3′-deoxythymidine (AZT) and 2′3′-dideoxyinosine (DDI). Despite being effective in inhibiting human immunodeficiency virus replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy, and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. Although cell surface–localized nucleoside transporters, such as human equilibrative nucleoside transporter 2 (hENT2) and human concentrative nucleoside transporter 1 (hCNT1), are known to increase the carrier-mediated uptake of 3′-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter (namely, hENT3) has been implicated in the mitochondrial transport of 3′-deoxy-nucleoside analogs. Using site-directed mutagenesis, generation of chimeric hENTs, and 3H-permeant flux measurements in mutant/chimeric RNA–injected Xenopus oocytes, here we identified the molecular determinants of hENT3 that dictate membrane translocation of 3′-deoxy-nucleoside analogs. Our findings demonstrated that whereas hENT1 had no significant transport activity toward 3′-deoxy-nucleoside analogs, hENT3 was capable of transporting 3′-deoxy-nucleoside analogs similar to hENT2. Transport analyses of hENT3-hENT1 chimeric constructs demonstrated that the N-terminal half of hENT3 is primarily responsible for the hENT3–3′-deoxy-nucleoside analog interaction. In addition, mutagenic studies identified that 225D and 231L in the N-terminal half of hENT3 partially contribute to the ability of hENT3 to transport AZT and DDI. The identification of the transporter segment and amino acid residues that are important in hENT3 transport of 3′-deoxy-nucleoside analogs may present a possible mechanism for overcoming the adverse toxicities associated with 3′-deoxy-nucleoside analog treatment and may guide rational development of novel nucleoside analogs.

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“…In agreement with this assumption, in large-scale cohort studies, the likelihood of TDF-associated renal dysfunction was found to vary depending upon the antiretrovirals being concurrently administered, with ritonavir-boosted protease inhibitors (PIs/r) being associated with the highest risk (3). Since only limited data on tenofovir exposure in patients are available (8) and in order to better understand the relationship between specific antiretrovirals and the drug pharmacokinetic profile, we carried out a cross-sectional pharmacokinetic survey in patients under successful and renally safe (estimated creatinine clearance [eCL CR ], Ͼ60 ml/min) chronic TDF administration.…”

mentioning

confidence: 99%

Tenofovir Plasma Concentrations According to Companion Drugs: a Cross-Sectional Study of HIV-Positive Patients with Normal Renal Function

Calcagno

Requena

Simiele

et al. 2013

Antimicrob Agents Chemother

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bAs the risk of tenofovir-associated renal toxicity has been found to be proportional to the drug plasma concentration, our aim was to measure the determinants of tenofovir plasma exposure in HIV-positive patients with normal renal function. A crosssectional analysis was conducted in HIV-positive patients chronically receiving tenofovir-containing highly active antiretroviral therapies (HAARTs). Patients on tenofovir-containing antiretroviral regimens, presenting 22 to 26 h after drug intake, having estimated glomerular filtration rates above 60 ml/min, reporting high adherence to antiretroviral medications (above 95% of the doses), and signing a written informed consent were included. Plasma tenofovir concentrations were measured through a validated high-performance liquid chromatography-mass spectrometry (HPLC/LC-MS) method. The tenofovir trough concentrations in 195 patients (median, 50 ng/ml, and interquartile range, 35 to 77 ng/ml) were significantly associated with the estimated glomerular filtration rate, body mass index, and third-drug class (protease-containing versus protease-sparing regimens) (with the highest exposure in unboosted-atazanavir recipients). The results of multivariate analysis showed that the third-drug class and the weight/creatinine ratio were independent predictors of tenofovir trough concentrations. This cross-sectional study shows that tenofovir trough concentrations are predicted by the weight/creatinine ratio and by the coadministered antiretrovirals, with protease inhibitors (whether boosted or unboosted) being associated with the highest plasma exposure. These data, previously available in healthy subjects or for some drugs only, could be useful for designing strategies to manage tenofovir-associated toxicity, since this toxicity has been reported to be dose dependent.

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Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs

Abstract: Knowledge of nucleoside analog reverse transcriptase inhibitor disposition intracellularly and extracellularly has expanded. This provides a basis for rational use of these agents clinically and adds new perspectives for future research.

Cited by 8 publications

References 50 publications

Pharmacologic Considerations for Preexposure Prophylaxis in Transgender Women

Pharmacologic Considerations for Preexposure Prophylaxis in Transgender Women

Identification of Structural and Molecular Features Involved in the Transport of 3′-Deoxy-Nucleoside Analogs by Human Equilibrative Nucleoside Transporter 3

Tenofovir Plasma Concentrations According to Companion Drugs: a Cross-Sectional Study of HIV-Positive Patients with Normal Renal Function

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