II-56 Paul Thoueille

Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration

Paul Thoueille (1), Susana Alves Saldanha (1), Vincent Desfontaine (1), Katharina Kusejko (2,3), Perrine Courlet (1), Pascal Andre (1), Matthias Cavassini (4), Laurent A. Decosterd (1), Thierry Buclin (1), Monia Guidi (1,5,6), The Swiss HIV Cohort Study

(1) Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Switzerland, (2) Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland, (3) Institute of Medical Virology, University of Zurich, Switzerland, (4) Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital and University of Lausanne, Switzerland, (5) Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Switzerland, (6) Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland

Objectives: 

Tenofovir alafenamide (TAF) is gradually replacing tenofovir disoproxil fumarate (TDF), both prodrugs of tenofovir (TFV), in HIV prevention and treatment. TAF is indeed better tolerated due to lower plasma levels of circulating TFV, which are associated with renal tubular lesions and, in the long term, with bone demineralization [1]. This project aims thus to characterize TFV pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under TAF in a real-life setting, while specifically assessing the impact of chronic kidney disease (CKD).

Methods: 

We conducted a population PK analysis with NONMEM® on 877 TFV and 100 TAF concentrations measured in 569 PLWH. A stepwise procedure allowed identifying the models best fitting first TAF and TFV data simultaneously, and then exclusively TFV data. The coadministration of cobicistat was forced into the model as a covariate affecting TAF relative bioavailability (F). The following covariates were tested for significance: age, sex, ethnicity, bodyweight, height, body mass index, serum creatinine, creatinine clearance (CLCR), estimated glomerular filtration rate (eGFR) and comedications. CLCR was calculated according to the Cockcroft & Gault equation [2], and eGFR to the CKD-EPI equations [3]. Concomitant drugs were classified as potent P-gp inhibitors, moderate P-gp inhibitors, P-gp inducers and OATP inhibitors. A “ceiling effect” for cobicistat inhibition (not included among the P-gp inhibitors), which would reduce the effect of P-gp inhibitors, was also investigated. Finally, model-based simulations allowed comparing TFV trough concentrations (Cmin), TFV and TAF PK profiles and areas under the curve, in patients having various levels of renal impairment: augmented kidney function (CLCR > 149 mL/min); normal kidney function (90-149 mL/min); stage 1 (60-89 mL/min); stage 2 (30-59 mL/min); stage 3 (15-29 mL/min); and stage 4 (<15 mL/min).

Results: 

A one-compartment model for TAF, with first order-absorption and elimination through complete conversion into TFV, and an additional compartment with linear elimation for TFV best described TAF and TFV data jointly. This model, assuming a fixed absorption rate constant of 2 h-1 for TAF, supports an almost immediate conversion of TAF into TFV, in accordance with the literature [4-6]. An identical description of TFV PK was deduced from the analysis of TFV data alone. TFV parameter estimates of the base PK model with variability (CV%) were an increase in TAF F by 106% (34%) under cobicistat, a volume of distribution of 2660 L, and a clearance of 40 L/h. Only CLCR appeared to have a clinically relevant impact on TFV clearance. The base model allowed estimating a TFV Tmax of 2.4 h, consistent with literature values [7-9], and a half-life of 46 h, slightly above the value of 32 h reported in the official monography [10]. Model-based simulations revealed 59%, 143%, 294% and 515% increases of median TFV Cmin in patients with stage 1, 2, 3 and 4 CKD, respectively, compared to patients with normal kidney function. Conversely, patients with augmented renal function had a 36% decrease in median TFV Cmin. In addition, model-based simulations showed that patients with stage 3 or 4 CKD had TFV Cmin levels similar to those observed after TDF administration in patients with normal kidney function [9].

Conclusions:

Our study indicates that CLCR is the main factor affecting circulating TFV exposure after TAF administration in PLWH. TFV levels, measured in routine therapeutic drug monitoring, are probably a predictor of systemic toxicity. It is however uncertain whether TAF dosage adaptation is suitable in PLWH with CKD, as TAF rather than TDF exposure drives drug entry into CD4+ lymphocytes, followed by intracellular formation of biologically active phosphorylated derivatives, and TAF exposure is not affected by CKD.

References:

  1. Benítez-Gutiérrez, L., et al., Treatment and prevention of HIV infection with long-acting antiretrovirals. Expert Rev Clin Pharmacol, 2018. 11(5): p. 507-517.
  2. Cockcroft, D.W. and M.H. Gault, Prediction of creatinine clearance from serum creatinine. Nephron, 1976. 16(1): p. 31-41.
  3. Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern Med, 2009. 150(9): p. 604-12.
  4. Compendium.ch. BIKTARVY cpr pell 50/200/25 mg. Approved by Swissmedic. Update March 2019.
  5. Cottrell, M.L., et al., Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother, 2017. 72(6): p. 1731-1740.
  6. Tenofovir alafenamide PK Fact Sheet. University of Liverpool. Prepared April 2019. https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/092/original/FactSheet_TAF_2019.pdf?1554892497.
  7. Yamada, H., et al., Pharmacokinetics of Tenofovir Alafenamide, Tenofovir, and Emtricitabine Following Administration of Coformulated Emtricitabine/Tenofovir Alafenamide in Healthy Japanese Subjects. Clin Pharmacol Drug Dev, 2019. 8(4): p. 511-520.
  8. Custodio, J.M., W. Garner, and C. Callebaut. The pharmacokinetics of tenofovir and tenofovir-diphosphate following administration of tenofovir alafenamide vs tenofovir disoproxil fumarate. in International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington, DC. 2015.
  9. Ruane, P.J., 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(4): p. 449-55.
  10. European Medicines Agency (EMA). BIKTARVY film-coated tablets. Summary of the product characteristics. https://www.ema.europa.eu/en/documents/product-information/biktarvy-epar-product-information_en.pdf.

Reference: PAGE 30 (2022) Abstr 10111 [www.page-meeting.org/?abstract=10111]

Poster: Clinical Applications

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