083: Pharmacokinetics of Tenofovir Alafenamide, Emtricitabine & Dolutegravir in a Patient on Peritoneal Dialysis

Statement of Purpose, Innovation or Hypothesis: 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. In this paper, we report a case of an HIV+ individual with ESKD on PD taking a daily tenofovir alafenamide, a TFV prodrug, (TAF)-containing regimen.

Description of Methods & Materials: A single-participant study was performed on the participant. We collected serial blood plasma and peripheral blood mononuclear cell (PBMC) at pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs after the observed dose of his daily medication; dolutegravir (DTG) 50 mg + TAF 25 mg/emtricitabine (FTC) 200 mg. Urine was also collected cumulatively over two time periods, 0-10 hrs, and 10-24 hrs post-dose. Pharmacokinetic parameters assessed included time until maximum plasma concentration (T_max), plasma peak concentration (C_max), the area under the curve up to the last quantifiable time-point (AUC_last) and minimum plasma concentration (C_min). These parameters were compared with published historical data from clinical trials in people living with HIV with normal kidney function and on hemodialysis. Drug concentrations were determined with liquid chromatographic-mass spectrometric (LC-MS/MS) analysis.

Data & Results: Plasma trough (C_min) concentrations of TAF, TFV, FTC and DTG were 0.05, 164, 1,006 and 718 ng/mL, respectively. Compared with PLWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while their AUC_last were 13.3- and 5.56-fold higher. Intracellular trough concentrations of TFV-DP and FTC-TP were 1.74- and 5.44- folds higher compared with PWH with normal kidney function. As for urine, TFV and FTC urine levels were 20 times lower than in people with normal GFR. TFV cumulative amount excreted (A_0-24) was 3.3 mg, which makes up 22% of the 15 mg of TFV provided by 25 mg of TAF. The TFV renal clearance was 14.1 mL/min. For FTC, (A_0-24) was 23.86 mg, which is 11.9% of total 200 mg dose, with renal clearance 8.93 mL/min. Lastly, DTG peak, trough, and AUC_last, measurements were lower in this participant than in people with normal kidney function. While the reason is not understood, his plasma trough concentrations were above 300 ng/mL, the median plasma trough concentrations established to be sufficient for viral suppression in the Phase 2 efficacy trial SPRING-1.

Interpretation, Conclusion or Significance: C_max and AUC of TAF in this participant were comparable with TAF concentrations in individuals with normal kidney function, likely due to the fact that TAF is not renally cleared to a significant degree. TFV concentrations were higher in the setting of PD, ranging from 11-fold (C_max) to 15-fold (C_min) higher compared to individuals with normal kidney function. this likely indicates plasma accumulation.

Disclosures: MGA is involved in litigation involving Gilead Sciences Inc.

Citations/References: 1. Swanepoel CR, Atta MG, D’Agati VD, Estrella MM, Fogo AB, Naicker S, et al. Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney International. 2018 Mar 1;93(3):545–59. 2. Zimmerman AM. Peritoneal dialysis: increasing global utilization as an option for renal replacement therapy. J Glob Health. 9(2):020316. 3. FDA. DESCOVY FDA Package Insert. 2016. 4. Dosing Recommendations for Drugs Used to Treat or Prevent Opportunistic Infections That Require Dosage Adjustment in Patients with Renal Insufficiency| NIH [Internet]. 2023 [cited 2023 Apr 30]. Available from: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/dosing-recommendations-drugs-used-ful 5. Gilead Sciences Inc. FDA CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW - SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS. 2014. 6. Podany AT, Bares SH, Havens J, Dyavar SR, O’Neill J, Lee S, et al. Plasma and intracellular pharmacokinetics of tenofovir in patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide. AIDS. 2018 Mar 27;32(6):761–5. 7. Gupta SK, Post FA, Arribas JR, Eron JJ, Wohl DA, Clarke AE, et al. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019 Jul 15;33(9):1455–65. 8. Custodio JM, Fordyce M, Garner W, Vimal M, Ling KHJ, Kearney BP, et al. Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment. Antimicrob Agents Chemother. 2016 Sep;60(9):5135–40. 9. Moltó J, Graterol F, Miranda C, Khoo S, Bancu I, Amara A, et al. Removal of Dolutegravir by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease. Antimicrob Agents Chemother. 2016 Apr;60(4):2564–6. 10. Aleman J, van den Berk GEL, Franssen EJF, de Fijter CWH. Tenofovir disoproxil treatment for a HIV-hepatitis B virus coinfected patient undergoing peritoneal dialysis: which dose do we need? AIDS. 2015 Jul 31;29(12):1579–80. 11. Eron JJ, Wilkin A, Ramgopal M, Osiyemi O, McKellar M, McKellar M, et al. A Daily Single Tablet Regimen (STR) of Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in Virologically-Suppressed Adults Living with HIV and End Stage Renal Disease on Chronic Hemodialysis. Open Forum Infect Dis. 2020 Dec 31;7(Suppl 1):S529–30. 12. Eron JJ, Lelievre JD, Kalayjian R, Slim J, Wurapa AK, Stephens JL, et al. Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: anen-label, s opingle-arm, multicentre, phase 3b trial. Lancet HIV. 2018 Dec 13;S2352-3018(18)30296-0. 13. Tucker GT. Measurement of the renal clearance of drugs. Br J Clin Pharmacol. 1981 Dec;12(6):761–70. 14. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Baltimore: Williams & Wilkins; 1995. 601 p. 15. Hummert P, Parsons TL, Ensign LM, Hoang T, Marzinke MA. Validation and implementation of liquid chromatographic-mass spectrometric (LC–MS) methods for the quantification of tenofovir prodrugs. Journal of Pharmaceutical and Biomedical Analysis. 2018 Apr;152:248–56. 16. Hendrix CW, Andrade A, Bumpus NN, Kashuba AD, Marzinke MA, Moore A, et al. Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066). AIDS Research and Human Retroviruses. 2016 Jan;32(1):32–43. 17. Dooley KE, Savic R, Gupte A, Marzinke MA, Zhang N, Edward VA, et al. Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial. Lancet HIV. 2020 Jun;7(6):e401–9. 18. FDA. TRUVADA FDA Package Insert. 2016. 19. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, et al. Phase I/II Trial of the Pharmacokinetics, Safety, and Antiretroviral Activity of Tenofovir Disoproxil  Fumarate in Human Immunodeficiency  Virus-Infected Adults. Antimicrob Agents Chemother. 2001 Oct;45(10):2733–9. 20. 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 Apr;57(4):1840–3. 21. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012 Feb;12(2):111–8. 22. Coleman JS, Diniz CP, Fuchs EJ, Marzinke MA, Aung W, Bakshi RP, et al. Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2023 Jan 1;92(1):89.

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