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Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines

The Pharmacogenomics Journal volume 16, pages 514–518 (2016)Cite this article

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Abstract

The HIV virus and hepatitis B virus nucleotide reverse transcriptase inhibitor tenofovir has been associated with proximal tubular toxicity; the latter was found to be predicted by plasma concentrations and with single-nucleotide polymorphisms in transporters-encoding genes. A cross-sectional analysis in adult HIV-positive patients with estimated creatinine clearance >60 ml min−1 was performed. Twelve-hour plasma and urinary tenofovir concentrations and single-nucleotide polymorphisms in several transporter-encoding genes were analysed. In 289 patients 12-h tenofovir plasma, urinary and urinary to plasma ratios were 69 ng ml−1 (interquartile range 51.5–95), 24.3 mg ml−1 (14.3–37.7) and 384 (209–560). At multivariate analysis estimated creatinine clearance, protease inhibitors co-administration and SLC28A2 CT/TT genotypes were independently associated with plasma tenofovir exposure; ABCC10 GA/AA genotypes and protease inhibitor co-administration were independently associated with the urinary to plasma tenofovir ratio. Tenofovir clearance was associated with genetic polymorphisms in host genes and with co-administered drugs: if confirmed by ongoing studies these data may inform treatment tailoring and/or dose reductions.

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References

  1. World Health Organization. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations, 2014. Available at: http://apps.who.int/iris/bitstream/10665/128048/1/9789241507431_eng.pdf?ua=1 (accessed 19 February 2015).

  2. Hall AM, Hendry BM, Nitsch D, Connolly JO . Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis 2011; 57: 773–780.

    Article  CAS  Google Scholar 

  3. Haverkort ME, van der Spek BW, Lips P, Slieker WA, ter Heine R, Huitema AD et al. Tenofovir-induced Fanconi syndrome and osteomalacia in two HIV-infected patients: role of intracellular tenofovir diphosphate levels and review of the literature. Scand J Infect Dis 2011; 43: 821–826.

    Article  CAS  Google Scholar 

  4. Tourret J, Deray G, Isnard-Bagnis C . Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J Am Soc Nephrol 2013; 24: 1519–1527.

    Article  CAS  Google Scholar 

  5. Baheti G, Kiser JJ, Havens PL, Fletcher CV . Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients. Antimicrob Agents Chemother 2011; 55: 5294–5299.

    Article  CAS  Google Scholar 

  6. Jackson A, Moyle G, Watson V, Tjia J, Ammara A, Back D et al. Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention. J Acquir Immune Defic Syndr 2013; 62: 275–281.

    Article  CAS  Google Scholar 

  7. Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K . Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 2007; 24: 811–815.

    Article  CAS  Google Scholar 

  8. Moss DM, Neary M, Owen A . The role of drug transporters in the kidney: lessons from tenofovir. Front Pharmacol 2014; 5: 248.

    Article  Google Scholar 

  9. Rodríguez-Nóvoa S, Labarga P, D'avolio A, Barreiro P, Albalate M, Vispo E et al. Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations. AIDS 2010; 24: 1064–1066.

    Article  Google Scholar 

  10. Poizot-Martin I, Solas C, Allemand J, Obry-Roguet V, Pradel V, Bregigeon S et al. Renal impairment in patients receiving a tenofovir-cART regimen: impact of tenofovir trough concentration. J Acquir Immune Defic Syndr 2013; 62: 375–380.

    Article  CAS  Google Scholar 

  11. Kerr SJ, Punyawudho B, Thammajaruk N, Colbers A, Chaiyahong P, Phonphithak S et al. Factors associated with daily tenofovir exposure in Thai subjects taking combination antiretroviral therapy. AIDS Res Hum Retroviruses 2015; 31: 368–374.

    Article  CAS  Google Scholar 

  12. Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM . Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther 2014; 19: 765–771.

    Article  CAS  Google Scholar 

  13. Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008; 83: 265–272.

    Article  CAS  Google Scholar 

  14. Calcagno A, Gonzalez de Requena D, Simiele M, D'Avolio A, Tettoni MC, Salassa B et al. Tenofovir plasma concentrations according to companion drugs: a cross-sectional study of HIV-positive patients with normal renal function. Antimicrob Agents Chemother 2013; 57: 1840–1843.

    Article  CAS  Google Scholar 

  15. Rodríguez-Nóvoa S, Labarga P, Soriano Egan D, Albalater M, Morello J et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis 2009; 48: e108–e116.

    Article  Google Scholar 

  16. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M et al. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis 2011; 204: 145–153.

    Article  CAS  Google Scholar 

  17. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T et al. Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study. Clin Infect Dis 2012; 55: 1558–1567.

    Article  CAS  Google Scholar 

  18. Ramamoorthy H, Abraham P, Isaac B . Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity. J Biochem Mol Toxicol 2014; 28: 246–255.

    Article  CAS  Google Scholar 

  19. Hall AM, Edwards SG, Lapsley M, Connolly JO, Chetty K, O'Farrell S et al. Subclinical tubular injury in HIV-infected individuals on antiretroviral therapy: a cross-sectional analysis. Am J Kidney Dis 2009; 54: 1034–1042.

    Article  Google Scholar 

  20. D'Avolio A, Sciandra M, Siccardi M, Baietto L, Gonzalez de Requena D, Bonora S et al. A new assay based on solid-phase extraction procedure with LC-MS to measure plasmatic concentrations of tenofovir and emtricitabine in HIV infected patients. J Chromatogr Sci 2008; 46: 524–528.

    Article  CAS  Google Scholar 

  21. Simiele M, Carcieri C, De Nicolò A, Ariaudo A, Sciandra M, Calcagno A et al. A LC-MS method to quantify tenofovir urinary concentrations in treated patients. J Pharm Biomed Anal 2015; 114: 8–11.

    Article  CAS  Google Scholar 

  22. Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV . Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 47: 298–303.

    Article  CAS  Google Scholar 

  23. Lubomirov R, Colombo S, di Iulio J, Ledergerber B, Martinez R, Cavassini M et al. Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis 2011; 203: 246–257.

    Article  CAS  Google Scholar 

  24. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS 2009; 23: 689–696.

    Article  CAS  Google Scholar 

  25. Mocroft A, Lundgren J, Ross M, Law M, Reiss P, Kirk O et al. A clinically useful risk-score for chronic kidney disease in HIV infection. J Int AIDS Soc 2014; 17: 19514.

    Article  Google Scholar 

  26. Owen RP, Gray JH, Taylor TR, Carlson EJ, Huang CC, Kawamoto M et al. Genetic analysis and functional characterization of polymorphisms in the human concentrative nucleoside transporter, CNT2. Pharmacogenet Genomics 2005; 15: 83–90.

    Article  CAS  Google Scholar 

  27. Nishimura T, Chishu T, Tomi M, Nakamura R, Sato K, Kose N et al. Mechanism of nucleoside uptake in rat placenta and induction of placental CNT2 in experimental diabetes. Drug Metab Pharmacokinet 2012; 27: 439–446.

    Article  CAS  Google Scholar 

  28. D'Avolio A, Ciancio A, Siccardi M, Smedile A, Simiele M, Cusato J et al. Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment. Ther Drug Monit 2012; 34: 722–728.

    Article  CAS  Google Scholar 

  29. Bleasby K, Castle JC, Roberts CJ, Cheng C, Bailey WJ, Sina JF et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica 2006; 36: 963–988.

    Article  CAS  Google Scholar 

  30. Kohler JJ, Hosseini SH, Green E, Abuin A, Ludaway T, Russ R et al. Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest 2011; 91: 852–858.

    Article  CAS  Google Scholar 

  31. Plosker GL . Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis. Drugs 2013; 73: 279–291.

    Article  CAS  Google Scholar 

  32. Nishijima T, Kawasaki Y, Tanaka N, Mizushima D, Aoki T, Watanabe K et al. Long-term exposure to tenofovir continuously decrease renal function in HIV-1-infected patients with low body weight: results from 10 years of follow-up. AIDS 2014; 28: 1903–1910.

    Article  CAS  Google Scholar 

  33. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y et al. Common clinical conditions — age, low BMI, ritonavir use, mild renal impairment — affect tenofovir pharmacokinetics in a large cohort of HIV-infected women. AIDS 2014; 28: 59–66.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a research grant from Gilead (Gilead Fellowship Program 2012, c2b35f7351).

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Authors and Affiliations

  1. Department of Medical Sciences, Unit of Infectious Diseases, University of Torino, Turin, Italy

    A Calcagno, J Cusato, L Marinaro, L Trentini, C Alcantarini, M Mussa, M Simiele, A D'Avolio, G Di Perri & S Bonora

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  1. A Calcagno
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Correspondence to A Calcagno.

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Competing interests

AC has received grants, travel grants and speaker’s honoraria from Abbvie, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Gilead Sciences, Viiv and Janssen-Cilag. SB has received grants, travel grants and consultancy fees from Abbvie, Boehringer-Inghelheim, BMS, Gilead Sciences, GlaxoSmithKline (GSK), MSD, Pfizer and Janssen-Cilag. GDP has received grants, travel grants and consultancy fees from Abbvie, Boehringer-Ingelheim, BMS, Gilead Sciences, GSK, MSD, Pfizer, Roche and Tibotec (Johnson & Johnson). The remaining authors declare no conflict of interest.

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Calcagno, A., Cusato, J., Marinaro, L. et al. Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines. Pharmacogenomics J 16, 514–518 (2016). https://doi.org/10.1038/tpj.2015.71

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