ABCC2*1C and plasma tenofovir concentration are correlated to decreased glomerular filtration rate in patients receiving a tenofovir-containing antiretroviral regimen

Manosuthi, Weerawat; Sukasem, Chonlaphat; Thongyen, Supeda; Nilkamhang, Samruay; Sungkanuparph, Somnuek

doi:10.1093/jac/dku129

Cited by 30 publications

(28 citation statements)

References 24 publications

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“…The results from multivariate analysis showed that tenofovir plasma concentrations are associated with body weight, eGFR, concomitant use of a ritonavir-boosted protease inhibitor, and the polymorphism ABCC4 4131T ¡ G. A lower patient body weight was associated with higher tenofovir plasma concentrations in our study. This finding is consistent with the results from previous studies which demonstrated that body weight is one of the important predictors of tenofovir's pharmacokinetics (4,15,17).…”

Section: Discussionsupporting

confidence: 93%

“…There is evidence of an association between tenofovir plasma concentrations and renal toxicity (4,6,7,14). A study by Rodríguez-Nóvoa et al has shown that patients with a tenofovir plasma concentration of more than 160 ng/ml at middose (10 to 14 h after the last dose) were at a 4.8 times higher risk of experiencing KTD than patients with a tenofovir plasma concentration below this cutoff value (6).…”

Section: Discussionmentioning

confidence: 99%

“…Five single nucleotide polymorphisms, ABCC2 Ϫ24C ¡ T (rs717620), ABCC2 1249G ¡ A (rs2273697), ABCC2 3972C ¡ T (rs3740066), ABCC4 3463A ¡ G (rs1751034), and ABCC4 4131T ¡ G (rs3742106), were genotyped. These polymorphisms were chosen on the basis of the allele frequency, evidence of their association with tenofovir plasma concentrations or toxicity, and their influence on drugs excreted via glomerular filtration and active tubular secretion (4,(9)(10)(11)(12).…”

Section: Study Populationmentioning

confidence: 99%

“…Previous studies have shown that the polymorphisms of ABCC2 and ABCC4 are associated with higher tenofovir concentrations (4,5) and a higher tenofovir plasma concentration is associated with renal impairment (6,7). The cutoff values of the middose (12-h) tenofovir concentration (C 12 ) and the trough (minimum) concentration (C min ) (Ͼ160 ng/ml and Ͼ90 ng/ml, respectively) were proposed to discriminate a risk of kidney tubular dysfunction (KTD) (6,7).…”

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confidence: 99%

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Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Rungtivasuwan

Avihingsanon

Thammajaruk

et al. 2015

Antimicrob Agents Chemother

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f Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged >18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ؎ 7.2 years. The mean tenofovir plasma concentration was 100.3 ؎ 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T ¡ G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.) T enofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir (TFV), is widely used for the treatment of human immunodeficiency virus (HIV) infection because of its high potency, good safety profile, limited drug interaction, and convenient once-daily dosing (1, 2). After absorption, TDF is rapidly converted to tenofovir. Tenofovir is then phosphorylated intracellularly to tenofovir diphosphate, an active analog, which inhibits HIV reverse transcriptase, resulting in a termination DNA chain elongation (1, 2).Tenofovir is eliminated by renal excretion through glomerular filtration and active tubular secretion. It is transported into kidney tubular cells by organic anion transporter 1 (OAT1) and OAT3, encoded by the SLC22A6 and SLC22A8 genes, respectively, at the basolateral membrane. Subsequently, tenofovir is secreted to the tubular lumen by multidrug-resistant protein 2 (MRP2) and MRP4, encoded by the ABCC2 and ABCC4 genes, respectively, at the apical membrane (3). Therefore, genetic polymorphisms of these transporter genes may affect the transport of tenofovir at ...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Study Populationmentioning

confidence: 99%

mentioning

confidence: 99%

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Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Rungtivasuwan

Avihingsanon

Thammajaruk

et al. 2015

Antimicrob Agents Chemother

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“…Tenofovir penetrates in tubular cells by several tubular transporters. Polymorphisms in genes encoding for tubular transporters organic cationic transporter 1, multidrug resistant protein 2 (MRP-2) and 4 (MRP-4) were associated with increased tenofovir plasma concentrations and increased risk of KTD or of decrease in eGFR [8][9][10][11].…”

mentioning

confidence: 99%

Preventing long-term tenofovir renal toxicity by pharmacokinetic assessment

Gagneux‐Brunon

Botelho-Nevers²,

Frésard³

et al. 2016

Aids

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Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients with Moderate‐to‐Severe Renal Impairment

Boonpeng,

Singkham,

Wutthikul

et al. 2024

The Journal of Clinical Pharma

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Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48‐96 h for moderate‐to‐severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV‐infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV‐infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration–time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once‐daily regimen achieved cumulative exposure comparable to the approved 300 mg every‐other‐day regimen. In severe renal impairment, TDF 75‐100 mg administered once daily provided similar cumulative exposure as 300 mg every 72‐96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72‐96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once‐daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

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ABCC2*1C and plasma tenofovir concentration are correlated to decreased glomerular filtration rate in patients receiving a tenofovir-containing antiretroviral regimen

Abstract: HIV-infected patients who carry ABCC2*1C genotype CC at position -24 or have high plasma tenofovir concentration are at risk of decreased glomerular filtration rate.

Cited by 30 publications

References 24 publications

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Preventing long-term tenofovir renal toxicity by pharmacokinetic assessment

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients with Moderate‐to‐Severe Renal Impairment

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