Plasma tenofovir trough concentrations are associated with renal dysfunction in Japanese patients with HIV infection: a retrospective cohort study

Kunimoto, Yusuke; Ikeda, Hiroshi; Fujii, Satoshi; Kitagawa, M.; Yamazaki, Kieko; Nakata, Hiromasa; Noda, Norimasa; Ishida, Tadao; Miyamoto, Atsushi

doi:10.1186/s40780-016-0056-5

Cited by 9 publications

(5 citation statements)

References 11 publications

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“…However, a study conducted among females showed that higher exposure to tenofovir in the vaginal tissue resulted in lower rates of HIV transmission 39 . On the contrary, tenofovir trough concentration was found to be associated with renal toxicity in Japanese HIV‐infected patients 40 . This study was conducted as an in vivo validation for an in vitro and translational exploratory investigation.…”

Section: Discussionmentioning

confidence: 96%

“…39 On the contrary, tenofovir trough concentration was found to be associated with renal toxicity in Japanese HIV-infected patients. 40 This study was conducted as an in vivo validation for an in vitro and translational exploratory investigation. However, the clinical data did not support our primary hypothesis, suggesting that renal influx trans-…”

Section: Discussionmentioning

confidence: 99%

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Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

Parvez

Kalkisim

Thu

et al. 2021

Brit J Clinical Pharma

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Aims: Tenofovir and para-aminosalicylic acid (PAS) may be coprescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the 2 drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics (PK).Methods: Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (OAT1 and OAT3). Later, we estimated clinical drug interactions using static and physiologically based PK modelling. Finally, we investigated the effects of PAScalcium formulation (PAS-Ca) on tenofovir disoproxil fumarate PK in healthy male Korean subjects.Results: PAS inhibited OAT1-and OAT3-mediated tenofovir uptake in vitro. The physiologically based PK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when coadministered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir PK showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (C max ) and area under the curve (AUC 0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. Conclusion:Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.drug-drug interactions, organic anion transporter, para-aminosalicylic acid, pharmacokinetics, tenofovir Md Masud Parvez and Said Kalkisim contributed equally for the manuscript.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

Parvez

Kalkisim

Thu

et al. 2021

Brit J Clinical Pharma

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“…Bloodstream TFV concentrations in the setting of daily adherence to TAF might be even higher, given that this individual was not at steady state. Further, the TFV accumulation observed in our PD patient led to TFV plasma trough concentration threefold those seen with daily TDF dosing, possibly mitigating any renal safety advantages conferred by TAF compared to TDF, as concentrations in this range have previously been linked to potential nephrotoxicity [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

Massih,

Atta,

Thio

et al. 2024

AIDS Res Ther

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Introduction Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. Methods A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. Results Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. Conclusions In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

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“…Rodríguez-Nóvoa et al demonstrated that impairment in the kidney tubular function in patients receiving tenofovir is associated with elevated plasma tenofovir concentrations 17. Kunimoto et al also demonstrated that TDF-induced renal impairment in Japanese HIV-infected patients may result from higher trough plasma tenofovir concentrations 21. Based on these findings, we hypothesise that the patient’s low body weight led to elevated plasma tenofovir concentrations and increased nephrotoxicity, resulting in decreased renal clearance and the further accumulation of plasma tenofovir.…”

Section: Discussionmentioning

confidence: 99%

Severe lactic acidosis during tenofovir disoproxil fumarate and cobicistat combination for HIV patient

Isoda,

Mihara,

Matsumoto

et al. 2023

BMJ Case Rep

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Lactic acidosis is a rare but serious side effect in individuals receiving nucleoside reverse transcriptase inhibitors. An underweight woman with HIV was admitted to our hospital because of nausea and diffuse myalgia. Her antiretroviral regimen had been changed to tenofovir disoproxil fumarate (TDF)/emtricitabine and darunavir/cobicistat 3 months prior, after which her renal function had gradually declined. After admission, she was diagnosed with lactic acidosis, and a liver biopsy suggested mitochondrial damage. Her plasma tenofovir levels were elevated at the onset of lactic acidosis. We hypothesise that the patient’s low body weight, combined with the addition of cobicistat, induced renal dysfunction and led to elevated plasma tenofovir concentrations, resulting in mitochondrial damage and lactic acidosis. Careful monitoring of renal function and lactic acidosis is required during use of TDF-containing regimens for underweight HIV patients, particularly when combined with cobicistat.

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Plasma tenofovir trough concentrations are associated with renal dysfunction in Japanese patients with HIV infection: a retrospective cohort study

Cited by 9 publications

References 11 publications

Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

Para‐aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

Severe lactic acidosis during tenofovir disoproxil fumarate and cobicistat combination for HIV patient

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