Browsing by Subject "tenofovir disoproxil fumarate"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Probenecid‐Boosted Tenofovir: A Physiologically‐Based Pharmacokinetic Model‐Informed Strategy for On‐Demand HIV Preexposure Prophylaxis
    (Wiley, 2020-01) Liu, Stephanie N.; Desta, Zeruesenay; Gufford, Brandon T.; Medicine, School of Medicine
    Multiple doses of tenofovir disoproxil fumarate (TDF) together with emtricitabine is effective for HIV preexposure prophylaxis (PrEP). TDF is converted to tenofovir (TFV) in circulation, which is subsequently cleared via tubular secretion by organic ion transporters (OATs; OAT1 and OAT3). Using in vitro kinetic parameters for TFV and the OAT1 and OAT3 inhibitor probenecid, a bottom‐up physiologically‐based pharmacokinetic model was successfully developed for the first time that accurately describes the probenecid–TFV interaction. This model predicted an increase in TFV plasma exposure by 60%, which was within 15% of the observed clinical pharmacokinetic data, and a threefold decrease in renal cells exposure following coadministration of a 600 mg TDF dose with 2 g probenecid. When compared with multiple‐dose regimens, a single‐dose probenecid‐boosted TDF regimen may be effective for HIV PrEP and improve adherence and safety by minimizing TFV‐induced nephrotoxicity by reducing TFV accumulation in renal cells.
  • Thumbnail Image
    Item
    Renal Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate: A Pooled Analysis of 26 Clinical Trials
    (Wolters Kluwer, 2019-03) Gupta, Samir K.; Post, Frank A.; Arribas, José R.; Eron, Joseph J., Jr.; Wohl, David A.; Clarke, Amanda E.; Sax, Paul E.; Stellbrink, Hans-Jürgen; Esser, Stefan; Pozniak, Anton L.; Podzamczer, Daniel; Waters, Laura; Orkin, Chloe; Rockstroh, Jürgen K.; Mudrikova, Tatiana; Negredo, Eugenia; Elion, Richard A.; Guo, Susan; Zhong, Lijie; Carter, Christoph; Martin, Hal; Brainard, Diana; Sengupta, Devi; Das, Moupali; Medicine, School of Medicine
    Objective: Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has been associated with improvement in markers of renal dysfunction in individual randomised trials; however the comparative incidence of clinically significant renal events remains unclear. Design: We used a pooled data approach to increase the person-years of drug exposure analysed, maximizing our ability to detect differences in clinically significant outcomes. Methods: We pooled clinical renal safety data across 26 treatment naïve and antiretroviral switch studies in order to compare the incidence of proximal renal tubulopathy (PRT) and discontinuation due to renal adverse events (AEs) between participants taking TAF-containing regimens versus those taking TDF-containing regimens. We performed secondary analyses from seven large randomised studies (two treatment-naïve and five switch studies) to compare incidence of renal AEs, treatment-emergent proteinuria, changes in serum creatinine, creatinine clearance, and urinary biomarkers (albumin, beta-2-microglobulin, and retinol binding protein to creatinine ratios). Results: Our integrated analysis included 9,322 adults and children with HIV (n = 6360 TAF, n = 2962 TDF) with exposure of 12,519 person-years to TAF and 5947 to TDF. There were no cases of PRT in participants receiving TAF versus 10 cases in those receiving TDF (p < 0.001), and fewer individuals on TAF (3/6360) versus TDF (14/2962) (p < 0.001) discontinued due to a renal AE. Participants initiating TAF- vs. TDF-based regimens had more favourable changes in renal biomarkers through 96 weeks of therapy. Conclusion: These pooled data from 26 studies, with over 12,500 person-years of follow-up in children and adults, support the comparative renal safety of TAF over TDF.