Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

Abstract

Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIVuninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, >90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (C max ) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUC inf ) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV C max and AUC inf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.T he availability of efficacious and well-tolerated antiretroviral agents and their coformulation into a single-tablet regimen (STR) for convenient dosing have transformed the treatment landscape and rendered HIV into a manageable disease (1). Indeed, several STRs have been approved for HIV treatment, including efavirenz (EFV)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF), rilpivirine (RPV)-FTC-TDF, elvitegravir (EVG)-cobicistat (COBI)-FTC-TDF, and, recently, abacavir (ABC)-dolutegravir (DTG)-lamivudine (3TC). Although STRs have been beneficial to a large number of HIV-infected patients, their use in special populations, such as those with end-organ dysfunction, has been limited due to the inability to alter the dose and the discordance in the doses of the various components with the different routes of elimination needed. Specifically, one or more components of the STRs mentioned above are predominantly if not exclusively renally eliminated [i.e., the nucleos(t)ide reverse transcriptase inhibitors TDF, FTC, and 3TC], necessitating dose reductions in patients with certain levels of renal impairment that is incompatible with fixed-dose-strength STR dosage forms. Therefore, patients with m...

Tenofovir alafenamide in the treatment of chronic hepatitis B: design, development, and place in therapy

“… 25 For patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15–29 mL/min), TFV exposure was significantly higher (26.4 vs 9.50 ng/mL) than for matched healthy patients with normal renal function (eGFR ≥90 mL/min). 26 However, the observed TFV exposure in treatment with TAF 25 mg for patients with severe renal impairment in this same study, was still lower than plasma TFV levels historically seen in pharmacokinetics studies with TDF as part of various antiretroviral regimens for HIV-infected patients with normal renal function. A study of the effect of food on TAF pharmacokinetics showed that TAF exposure was decreased under fasted compared to fed conditions.…”

Establishment of HK-2 Cells as a Relevant Model to Study Tenofovir-Induced Cytotoxicity

“…The concentrations used in our current study are clinically relevant as plasma TFV concentrations have been reported to be 2.2 μM in HIV-1 infected patients [4,8]. Additionally, TFV plasma concentrations are higher in HIV-1 patients and non-infected individuals with existing renal impairment; patients with renal impairment also experience a longer duration of TFV exposure, as shown by a 15-fold increase in AUC 0–24h [21,26,27]. Therefore, HK-2 cells provide a model that can be used to examine the mechanism of toxicity without the compounding physiological parameters influencing the response of the kidney to a toxicant.…”

Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

“…Decreased TFV systemic clearance estimates observed with TAF administration are most likely due to flip-flop kinetics, in which the formation and systemic distribution of TFV is the slower, rate-limiting step and is reflected in the concentration-time profile as the elimination rate. TFV has been measured in urine after TAF administration, 20 and thus it is unlikely that it is cleared by any process other than renal elimination, as observed with TDF-generated TFV. Given this, these clearance estimates should be interpreted with caution.…”