Antiviral Therapy 2014; 19: (doi: /IMP2770)
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1 Antiviral Therapy 2014; 19: (doi: /IMP2770) Short communication Tenofovir alafenamide is not a substrate for renal organic anion transporters (ATs) and does not exhibit AT-dependent cytotoxicity Rujuta A Bam 1, Stephen R Yant 1 *, Tomas Cihlar 1 1 Gilead Sciences, Biology Department, Foster City, CA, USA *Corresponding author stephen.yant@gilead.com Background: Tenofovir alafenamide () is a novel prodrug of tenofovir that shows enhanced antiretroviral effect and reduced plasma tenofovir exposures at approximately one-tenth the clinically approved dose of tenofovir disoproxil fumarate (TDF). Tenofovir released from TDF undergoes active renal secretion via organic anion transporters (AT1 and AT3), leading to higher exposure of renal proximal tubules to tenofovir and a potential for renal adverse effects in a small subset of TDF-treated patients. Here, we evaluate the interaction of with AT1 and AT3 to assess the potential for its active accumulation in proximal tubules. Methods: AT-mediated transport and cytotoxicity (CC 50 ) of and tenofovir were assessed in cells expressing ATs and compared with matched transporter-null cells. Results: While AT1 and AT3 expression increased tenofovir cellular uptake by >70-fold and 8.2-fold, respectively, the expression of either AT did not significantly change intracellular accumulation under identical conditions. In addition, although tenofovir was significantly more cytotoxic in AT1- and AT3- expressing cells (>21 and >3.6 fold change in CC 50 values, respectively), in vitro cytotoxicity showed little to no change upon overexpression of either renal transporter ( fold change in CC 50 ). Conclusions: Unlike tenofovir, does not interact with renal transporters AT1 or AT3 and exhibits no ATdependent cytotoxicity. is thus unlikely to actively accumulate in renal proximal tubules in an AT-dependent manner, supporting the potential for an improved renal safety profile. Introduction Tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir () widely used for the treatment of HIV-1 infection, is rapidly metabolized in plasma, resulting in a fast systemic release of the parent nucleotide. As a result of its fast systemic hydrolysis, intact TDF is not detected in patient plasma at any time post-dosing [1], indicating that the kidney is exposed primarily to parent, but not intact TDF. Parent undergoes renal secretion by a combination of glomerular filtration and active tubular secretion via organic anion secretion pathway [1]. Human renal organic anion transporters 1 (AT1) and 3 (AT3) are selectively expressed on the basolateral side of renal proximal tubule cells (PTCs) [2] and mediate the active uptake of into PTCs [3,4] (Figure 1). is excreted into the urine via the multidrug resistance protein 4 (MRP4), an efflux pump present on the apical membrane of PTCs [5]. The active renal transport of acyclic nucleotides via AT1 and AT3 may promote their dose-dependent accumulation in PTCs, as was observed in several animal species [6,7], and likely represents the primary aetiological factor that is prerequisite for the development of the renal dysfunction observed in a small subset of TDF-treated patients [8,9]. Tenofovir alafenamide (; formerly GS-7340) is a new prodrug of undergoing Phase III clinical testing in combination with emtricitabine and cobicistat-boosted elvitegravir. Phase Ib monotherapy studies in HIV- 1-infected patients demonstrated a higher magnitude of viral suppression at 25 mg compared with the approved clinical 300 mg TDF dose [10]. In subsequent Phase II, in combination with emtricitabine and cobicistat-boosted elvitegravir showed similar efficacy, but reduced renal and bone effects compared with TDF in combination with emtricitabine and cobicistat-boosted elvitegravir following 48 weeks of treatment [11] International Medical Press (print) (online) 687
2 RA Bam et al. Figure 1. Active renal elimination of originating from TDF or A GI tract Gut wall Systemic circulation Renal epithelial cell H 2 TDF B P TDF (ester prodrug of tenofovir) 300 mg once daily rapid AT1 AT3 MRP4 H 2 H P slow AT1? AT3 (amidate prodrug of tenofovir) mg once daily AT1 AT3 MRP4 Blood (basolateral) Active tubular secretion Urine (apical) (A) Tenofovir disoproxil fumarate (TDF; administered at 300 mg once daily) is rapidly hydrolysed in plasma after oral administration and intestinal absorption, resulting in minimal circulating levels of intact TDF, but relatively high systemic levels of parent tenofovir () that undergoes subsequent active renal elimination. In this process, is taken up via organic anion transporters organic anion transporters (AT)1 and AT3 selectively expressed on the basolateral membrane of renal proximal tubule cells (PTCs) followed by its excretion into the urine by multidrug resistance protein 4 (MRP4), an efflux pump present on the apical membrane of PTCs. (B) Tenofovir alafenamide () is administered at a substantially lower dose (10 25 mg once daily) compared with TDF and exhibits prolonged stability in plasma, which enables more effective delivery of parent into target T-lymphocytes and lymphatic tissues. At the same time, the lower dose of results in reduced systemic levels of. Although generated from either TDF or undergoes the same active renal elimination, lower systemic levels of translate into reduced renal exposure to the drug and potentially an improved renal safety profile of relative to TDF. The goal of the present study (highlighted in red) was to determine if the systemically circulating intact might contribute to the accumulation of in PTCs via interaction with the AT1 and/or AT3 pathway as this could potentially diminish the renal safety benefit expected from the low dose of. GI, gastrointestinal. In comparison to TDF, exhibits prolonged stability in plasma, but undergoes fast conversion to parent inside target cells via hydrolysis by intracellular protease cathepsin A [12]. Thus, more effectively delivers the parent into lymphatic cells and tissues, which allows for the administration of a reduced dose of compared with TDF [13]. As compared with the approved clinical dose of TDF, the low investigational dose of leads to approximately 90% reduction in systemic levels while still producing 5 7-fold higher concentrations of the active metabolite diphosphate in blood lymphocytes [10]. The reduced systemic exposure of free is expected to decrease its renal uptake and accumulation, which may potentially improve the long-term renal safety profile of relative to TDF. However, since intact, but not TDF, is present systemically following its oral dosing, it is important to understand its interaction with renal transport pathways involved in the renal uptake of parent. It is currently unknown whether the presence of intact in the periphery might contribute to the accumulation of in PTCs via interaction with the AT pathway. Indeed, if were found to be an effective substrate for ATs, then the expected International Medical Press
3 is not a substrate for renal organic anion transporters renal safety benefit of its reduced dose relative to TDF could be diminished due to preferential uptake of circulating into renal proximal tubules. Therefore, we performed an in vitro assessment of transport by ATs and potential resulting AT-mediated cytotoxicity of relative to the parent (Figure 1). Methods Compounds and were synthesized by Gilead Sciences (Foster City, CA, USA). [ 3 H] and [ 14 C] were purchased from Moravek Biochemicals (Brea, CA, USA). Probenecid was purchased from Sigma (St Louis, M, USA). Plasmids and cells Mammalian expression plasmids for human AT1 and AT3 were obtained from rigene (Rockville, MD, USA). The pcda3.1(+) plasmid used for control transfections was purchased from Invitrogen (Carlsbad, CA, USA). Human epithelial kidney (HEK) 293T cells were obtained from the Gladstone Institute (San Francisco, CA, USA), maintained in DMEM medium (Invitrogen) supplemented with 10% fetal bovine serum and grown at 37ºC in a 5% C 2 incubator with 90% humidity. HEK293T cells were transiently transfected in bulk with pcda-null, pcda-at1 or pcda-at3 expression plasmids as recommended by the manufacturer. 24 h post-transfection, cells were trypsinized and seeded on poly-d-lysine coated 12-well plates (BD Sciences, San Jose, CA, USA) at cells/well for transport assays, or on poly-d-lysine coated 96-well plates (VWR, Pittsburgh, PA, USA) at cells/well for cytotoxicity assays. Cell lines stably expressing human AT1 (CH AT1 ), human AT3 (BHK AT3 ) and matched control cells (CH pires, BHK pires ) have been previously described [14 16]. Studies utilizing stable cell lines were directly plated and assayed in an identical manner. AT transport assays AT and null-expressing cells were incubated with 1 mm [ 3 H] or [ 14 C] with or without 50 mm probenecid for 2 h at 37ºC and the intracellular level of [ 3 H] and [ 14 C] quantified as previously described [15]. A measure of AT-dependent uptake for each radiolabelled substrate, expressed relative to that observed in mock-transfected cells, was assessed in two independent experiments performed in triplicate. Cytotoxicity assays AT and null-expressing cells were incubated with 100 ml DMEM containing serially diluted or (1% final DMS concentration) for 4 days at 37 C. Each well then received 100 ml CellTiter Glo (Promega, Madison, WI, USA) and the luminescence signals were quantified on an Envision plate reader (Perkin-Elmer, Waltham, MA, USA). The drug concentration associated with a 50% decrease in cell viability (CC 50 value) was calculated from triplicate well measurements by nonlinear regression analysis using XLfit TM software (IDBS, Guildford, Surrey, UK). CC 50 values (mean ±sd) were obtained from five independent experiments performed in triplicate. Results transport by renal organic anion transporters AT1 and AT3 We measured the intracellular accumulation of and in vitro using human epithelial kidney-derived HEK293T cells expressing human AT1 or AT3. Studies using either a transient or stable expression system produced similar results and showed that in contrast to, did not show increased accumulation in transporter-expressing cells relative to their matched transporter-null control cells (Figure 2A and 2B). In addition, although intracellular levels were profoundly reduced in the presence of the AT inhibitor probenecid, the low-level accumulation observed in transporter-expressing cells remained essentially unchanged by probenecid treatment (Figure 2C and 2D). These results indicate that while is an effective substrate for AT1 and, to a lesser extent, AT3 transporters, does not undergo active transport in human cells expressing either renal transporter, suggesting that systemic intact is unlikely to undergo preferential accumulation in PTCs following its oral administration. cytotoxicity in AT-expressing cells AT1 expression has been previously shown to induce the cytotoxicity of by enhancing its intracellular accumulation [16]. Consistent with those findings, we observed a >21-fold and >3.6-fold increase in cytotoxicity in cells transiently expressing functional AT1 and AT3, respectively, when compared with control transporter-null cells exposed to at its solubility limit of 2 mm (Table 1). As expected, the cytotoxicity for was higher in control cells due to its greater cellular permeability relative to. However, cytotoxicity was not significantly changed in AT1-expressing cells, further indicating that is not a substrate for AT1. Although we did observe a minor increase in the CC 50 value for in AT3-expressing cells, additional time-course studies indicated that this effect occurred independent of any concomitant increase in intracellular levels (Additional file 1). In addition, we observed similar changes in the cytotoxicity of other small-molecule agents that are not transported by AT3 (puromycin and gemcitabine; Additional file 1), further suggesting that intracellular accumulation Antiviral Therapy
4 RA Bam et al. Figure 2. Intracellular accumulation of and in cells expressing AT transporters A Fold change in intracellular accumulation Transient AT expression Control AT1 AT3 B Fold change in intracellular accumulation Stable AT expression Control AT1 AT3 C 7 Tenofovir D 0.6 Intracellular accumulation of 3H-, pmol/million cells AT1 + PBC AT3 Intracellular accumulation of 14C-, pmol/million cells AT1 + PBC AT3 Intracellular accumulation was measured by scintillation counting following the incubation of cells with 1 mm radiolabelled tenofovir () or tenofovir alafenamide (). The compound uptake was determined in cells (A) transiently or (B) stably expressing organic anion transporters (AT)1 or AT3. umbers above each bar represent fold change in the intracellular accumulation of tested compounds relative to control cells lacking the AT activity. Data represent mean values obtained from three independent experiments performed in duplicate. Cells transiently overexpressing AT1 or AT3 were incubated with 1 mm radiolabelled (C) or (D) in the presence or absence of 50 mm AT inhibitor probenecid (PBC) for 2 h. Intracellular accumulation of compounds data represent the mean ±sd from at least two independent experiments performed in triplicate. Table 1. Effect of AT expression on the in vitro cytotoxicity and selectivity of and CC 50, mm a (fold change) b Selectivity index Selectivity index Compound Control AT1 AT3 HIV-1 EC 50, mm c (AT1) d (AT3) d >2,000 (1.0) 94 ±71 (>21.3) 553 ±174 (>3.6) 6.7 ± ±42 (1.0) 319 ±56 (0.5) 47 ±17 (3.5) ± ,000 4,270 a HEK293T cells transiently overexpressing renal transporters were incubated with serial dilutions of tenofovir () or tenofovir alafenamide () for 4 days and 50% decrease in cell viability (CC 50 ) values were determined using a CellTiter Glo cell viability readout (Promega, Madison, WI, USA). Data represent the mean ±sd from five independent experiments performed in triplicate. b Fold change in CC 50 values relative to control transporter-null cells (control CC 50 /AT CC 50 ). c Activated primary human CD4 + T-lymphocytes were infected with pseudotyped HIV-1 containing luciferase reporter and incubated with serial dilutions of or. 50% Effective concentration (EC 50 ) was calculated 3 days after infection from ne-glo based relative luminescent units measurements of infectivity [18]. d Selectivity index (CC 50 /EC 50 ) is calculated using cytotoxicity measurements (CC 50 ) from human embryonic kidney (HEK293T) cells expressing AT1 or AT3 and antiviral activity measurements (EC 50 ) from CD4 + T-lymphocytes. AT, organic ion transporters. and cytotoxicity is not specifically influenced by AT3 dependent transport. Collectively, these results indicate that unlike, does not interact with renal transporters AT1 or AT3, and exhibits no AT-dependent effect on cell viability. In vitro selectivity of Since the antiretroviral efficacy and renal toxicity of manifest in profoundly different cell types and tissues, we aimed to assess the selectivity of and by determining the antiviral activity and cytotoxicity International Medical Press
5 is not a substrate for renal organic anion transporters of the compounds in the respective cell types that are physiologically relevant for these effects. We have tested the selectivity of and as a ratio of their in vitro cytotoxicity in AT-expressing renal HEK293T cells relative to their anti-hiv activity in primary CD4 + T-lymphocytes. Importantly, exhibits much higher selectivity than the parent when the effect on the viability of AT-expressing renal cells is considered in the context of their antiretroviral activity in primary T-cells (Table 1). Discussion egatively charged antiviral nucleotide analogues including are substrates for the renal organic anion transporters AT1 and AT3, leading to active transport into PTCs [16,17]. This anion-selective uptake potentially affects renal functions in a manner dependent on their dose and intrinsic cytotoxicity [3]. Since the new investigational prodrug exhibits prolonged stability in blood plasma compared with TDF, we assessed its potential for active renal accumulation by investigating its interactions with AT1 and AT3. The in vitro studies presented herein indicate that unlike parent, does not interact with the tested ATs and thus is unlikely to be preferentially taken up by PTCs. This is consistent with preclinical findings by Lee et al. [13] showing that equimolar doses of and TDF result in similar renal accumulation of despite the presence of significant levels of intact in plasma, indicating that the additional systemic exposure to does not contribute to the renal accumulation of parent. Therefore, even though administration still generates systemic, some of which will be taken up by PTCs via an AT-mediated mechanism, the clinical administration of a substantially reduced effective dose of relative to that of TDF should result in proportionally lower systemic levels of the parent nucleotide [10]. Indeed, Phase Ib monotherapy studies in HIV-infected patients demonstrated that relative to 300 mg TDF, a 25 mg dose results in an 86% decrease in circulating plasma levels while exhibiting increased anti-hiv-1 activity due to a higher accumulation of diphosphate levels in lymphocytes [10]. In the absence of active ATmediated uptake of intact, the lower blood levels of parent should translate into overall reduced renal exposure to the compound. While the long-term clinical renal safety profile of is currently unknown, it is noteworthy that in a subsequent Phase II study, patients receiving in combination with emtricitabine and cobicistat-boosted elvitegravir experienced smaller elevations in serum creatinine levels and less tubular proteinuria as compared with those receiving TDF with the same background regimen [11]. Thus, our present observations that does not interact with AT1 or AT3, combined with data demonstrating that reduced doses of result in proportionally lower systemic levels of, indicate potential for an improved renal safety profile of relative to TDF and further support the development of as a new antiretroviral agent. Acknowledgements We thank Kirsten Stray and Gabriel Birkus for technical advice, and Michael Miller for his input in manuscript preparation. Author contributions: performed experiments (RB), study design, data analysis and manuscript preparation (RB, SY and TC). Disclosure statement All authors are employees of Gilead Sciences, Inc. Additional file Additional file 1: A supplementary table showing cytotoxicity and intracellular accumulation in AT3- expressing cells over time can be found at intmedpress.com/uploads/documents/3173_bam_ Additional_file.pdf References 1. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 2004; 43: Motohashi H, Sakurai Y, Saito H, et al. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc ephrol 2002; 13: Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1 (hat1) and its role in the nephrotoxicity of antiviral nucleotide analogs. ucleosides ucleotides ucleic Acids 2001; 20: Cihlar T, Bleasby K, Roy A, Pritchard J. Antiviral acyclic nucleotide analogs tenofovir and adefovir are substrates for kidney organic anion, but not cation transporters: Implications for renal drug interactions. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. 30 ctober 2 ovember 2004, Washingtion DC, USA. Abstract A van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary camp and cgmp. J Am Soc ephrol 2002; 13: Cundy KC, Bidgood AM, Lynch G, Shaw JP, Griffin L, Lee WA. Pharmacokinetics, bioavailability, metabolism, and tissue distribution of cidofovir (HPMPC) and cyclic HPMPC in rats. Drug Metab Dispos 1996; 24: Cundy KC, Li ZH, Lee WA. Effect of probenecid on the distribution, metabolism, and excretion of cidofovir in rabbits. Drug Metab Dispos 1996; 24: Sax PE, Gallant JE, Klotman PE. Renal safety of tenofovir disoproxil fumarate. 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6 RA Bam et al. 10. Ruane PJ, Dejesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide () as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr 2013; 63: Sax P, Brar I, Elion R, et al. 48 week study of tenofovir alafenamide () versus tenofovir disoproxil fumarate (TDF), each in a single tablet regimen (STR) with elvitegravir, cobicistat, and emtricitabine [E/C/F/ versus E/C/F/TDF] for initial HIV treatment. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy September 2013, Denver, C, USA. Abstract H-1464d. 12. Birkus G, Wang R, Liu X, et al. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS Antimicrob Agents Chemother 2007; 51: Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005; 49: Accepted 15 March 2014; published online 4 April Cihlar T, Ray AS, Laflamme G, et al. Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors. Antivir Ther 2007; 12: Cihlar T, Laflamme G, Fisher R, et al. ovel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother 2009; 53: Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K. Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hat1, hat3, and hct2). Pharm Res 2007; 24: Ho ES, Lin DC, Mendel DB, Cihlar T. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc ephrol 2000; 11: Bam RA, Birkus G, Babusis D, Cihlar T, Yant SR. Metabolism and antiretroviral activity of tenofovir alafenamide in CD4 + T-cells and macrophages from demographically diverse donors. Antivir Ther 2014; doi: /imp International Medical Press
Received 5 September 2008/Returned for modification 17 October 2008/Accepted 28 October 2008
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 2009, p. 150 156 Vol. 53, No. 1 0066-4804/09/$08.00 0 doi:10.1128/aac.01183-08 Copyright 2009, American Society for Microbiology. All Rights Reserved. Novel
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