Pharmacology: Mechanism of Action:
Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology as follows].
The pharmacokinetics of TDF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
TENOFOVIR DISOPROXIL FUMARATE is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from TENOFOVIR DISOPROXIL FUMARATE in fasted subjects is approximately 25%. Following oral administration of a single dose of TENOFOVIR DISOPROXIL FUMARATE 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax
) are achieved in 1.0 ± 0.4 hrs. Cmax
and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg·hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a TENOFOVIR DISOPROXIL FUMARATE dose range of 75 to 600 mg and are not affected by repeated dosing.
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax
of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination:
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of TENOFOVIR DISOPROXIL FUMARATE, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of TENOFOVIR DISOPROXIL FUMARATE 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption:
Administration of TENOFOVIR DISOPROXIL FUMARATE 300 mg tablets following a high-fat meal (~700 to 1,000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞
of approximately 40% and an increase in Cmax
of approximately 14%. However, administration of TENOFOVIR DISOPROXIL FUMARATE with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax
by approximately 1 hour. Cmax
and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg·hr/mL following multiple doses of TENOFOVIR DISOPROXIL FUMARATE 300 mg once daily in the fed state, when meal content was not controlled.
Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Gender: Tenofovir pharmacokinetics are similar in male and female subjects.
Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Renal Impairment: The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see New Onset or Worsening Renal Impairment under Precautions]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax
, and AUC0-∞
of tenofovir were increased (Table 1). (See Table 1.)
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Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of TENOFOVIR DISOPROXIL FUMARATE have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in TENOFOVIR DISOPROXIL FUMARATE dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions: At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.
TENOFOVIR DISOPROXIL FUMARATE has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 2 and 3 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TENOFOVIR DISOPROXIL FUMARATE on the pharmacokinetics of coadministered drug.
TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.
No clinically significant drug interactions have been observed between TENOFOVIR DISOPROXIL FUMARATE and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir. (See Table 2.)
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No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TENOFOVIR DISOPROXIL FUMARATE: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine. (See Table 3.)
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Microbiology: Mechanism of Action:
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Activity against HIV:
Antiviral Activity: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50
(50% effective concentration) values for tenofovir were in the range of 0.04 μM to 8.5 μM. In drug combination studies, tenofovir was not antagonistic with HIV-1 NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine), NNRTIs (efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50
values ranged from 0.5 μM to 2.2 μM) and strain-specific activity against HIV-2 (EC50
values ranged from 1.6 μM to 5.5 μM).
Resistance: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 4-fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.
In Trial 903 of treatment-naïve subjects (TENOFOVIR DISOPROXIL FUMARATE+3TC+EFV versus d4T+3TC+EFV), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of EFV and 3TC resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) of analyzed patient isolates in the TENOFOVIR DISOPROXIL FUMARATE arm and in 2/49 (4%) of analyzed patient isolates in the d4T arm. Of the 8 subjects whose virus developed K65R in the TENOFOVIR DISOPROXIL FUMARATE arm through 144 weeks, 7 occurred in the first 48 weeks of treatment and one at Week 96. One patient in the TENOFOVIR DISOPROXIL FUMARATE arm developed the K70E substitution in the virus. Other substitutions resulting in resistance to TENOFOVIR DISOPROXIL FUMARATE were not identified in this trial.
In Trial 934 of treatment-naïve subjects (TENOFOVIR DISOPROXIL FUMARATE+FTC+EFV versus AZT/3TC+EFV), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with >400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of EFV resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to FTC and 3TC, was observed in 2/19 of analyzed subject isolates in the TENOFOVIR DISOPROXIL FUMARATE+FTC group and in 10/29 of analyzed subject isolates in the AZT/3TC group. Through 144 weeks of Trial 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
Cross Resistance: Cross resistance among certain HIV-1 NRTIs has been recognized. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected subjects treated with abacavir or didanosine. HIV-1 isolates with this substitution also show reduced susceptibility to FTC and 3TC. Therefore, cross resistance among these drugs may occur in patients whose virus harbors the K65R or K70E substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of three AZT-associated RT substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
In Trials 902 and 907 conducted in treatment-experienced subjects (TENOFOVIR DISOPROXIL FUMARATE + Standard Background Therapy (SBT) compared to placebo + SBT), 14/304 (5%) of the TENOFOVIR DISOPROXIL FUMARATE-treated subjects with virologic failure through Week 96 had >1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 RT gene.
The virologic response to TENOFOVIR DISOPROXIL FUMARATE therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Trials 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross resistance of TENOFOVIR DISOPROXIL FUMARATE to pre-existing AZT resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. TENOFOVIR DISOPROXIL FUMARATE-treated subjects whose HIV-1 expressed 3 or more AZT resistance-associated substitutions that included either the M41L or L210W RT substitution showed reduced responses to TENOFOVIR DISOPROXIL FUMARATE therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to TENOFOVIR DISOPROXIL FUMARATE therapy. Subjects whose virus expressed an L74V substitution without AZT resistance-associated substitutions (N=8) had reduced response to TENOFOVIR DISOPROXIL FUMARATE. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
In the protocol defined analyses, virologic response to TENOFOVIR DISOPROXIL FUMARATE was not reduced in subjects with HIV-1 that expressed the abacavir/FTC/3TC resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
Trials 902 and 907 Phenotypic Analyses: Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to TENOFOVIR DISOPROXIL FUMARATE and response to TENOFOVIR DISOPROXIL FUMARATE therapy. Table 4 summarizes the HIV-1 RNA response by baseline TENOFOVIR DISOPROXIL FUMARATE susceptibility. (See Table 4.)
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Activity against HBV:
Antiviral Activity: The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50
values for tenofovir ranged from 0.14 to 1.5 μM, with CC50
(50% cytotoxicity concentration) values >100 μM. In cell culture combination antiviral activity studies of tenofovir with HBV NrtIs entecavir, lamivudine, and telbivudine, and with the HIV-1 NRTI emtricitabine, no antagonistic activity was observed.
Resistance: Cumulative TENOFOVIR DISOPROXIL FUMARATE genotypic resistance has been evaluated annually for up to 384 weeks in Trials 0102, 0103, 0106, 0108, and 0121 with the paired HBV rt amino acid sequences of the pretreatment and on-treatment isolates from subjects who received at least 24 weeks of TENOFOVIR DISOPROXIL FUMARATE monotherapy and remained viremic with HBV DNA ≥400 copies/mL (69 IU/mL) at the end of each study year (or at discontinuation of TENOFOVIR DISOPROXIL FUMARATE monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Trials 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on TENOFOVIR DISOPROXIL FUMARATE monotherapy (15% versus 5%, respectively).
HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 5); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to TENOFOVIR DISOPROXIL FUMARATE (genotypic and phenotypic analyses). (See Table 5.)
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Cross Resistance: Cross resistance has been observed between HBV NrtIs.
In cell-based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine (3TC) and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
One hundred fifty-two subjects initiating TENOFOVIR DISOPROXIL FUMARATE therapy in Trials 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV NrtIs: 14 with adefovir resistance- associated substitutions (rtA181S/T/V and/or rtN236T), 135 with 3TC resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and 3TC resistance-associated substitutions. Following up to 384 weeks of TENOFOVIR DISOPROXIL FUMARATE treatment, 10 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with 3TC-resistant HBV, and 2 of the 3 subjects with both adefovir- and 3TC-resistant HBV achieved and maintained virologic suppression (HBV DNA <400 copies/mL [69IU/mL]). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.