CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD in fasted patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 296 ± 90 ng/mL and 2287 ± 685 ng∙hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by repeated dosing.
Effects of Food on Oral Absorption
Administration of VIREAD following a high-fat meal (~700 to 1000 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 VIREAD 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 326 ± 119 ng/mL and 3324 ± 1370 ng∙hr/mL following multiple doses of VIREAD 300 mg once daily in the fed state, when meal content was not controlled.
Distribution
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 CYP450 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 VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of VIREAD 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.
Special Populations
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
Tenofovir pharmacokinetics are similar in male and female patients.
Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly (>65 years).
The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in VIREAD dosing is required in patients with hepatic impairment.
The pharmacokinetics of tenofovir are altered in patients with renal impairment (see WARNINGS, Renal Impairment). In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0– ∞ of tenofovir were increased (Table 2). It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis (see DOSAGE AND ADMINISTRATION).
Table 2 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir300 mg, single dose of VIREAD in Patients with Varying Degrees of Renal Function | Baseline Creatinine Clearance (mL/min) | >80
(N=3) | 50–80
(N=10) | 30–49
(N=8) | 12–29
(N=11) |
|---|
| Cmax (ng/mL) | 335.4 ± 31.8 | 330.4 ± 61.0 | 372.1 ± 156.1 | 601.6 ± 185.3 |
| AUC 0–∞ (ng∙hr/mL) | 2184.5 ± 257.4 | 3063.8 ± 927.0 | 6008.5 ± 2504.7 | 15984.7 ± 7223.0 |
| CL/F (mL/min) | 1043.7 ± 115.4 | 807.7 ± 279.2 | 444.4 ± 209.8 | 177.0 ± 97.1 |
| CLrenal (mL/min) | 243.5 ± 33.3 | 168.6 ± 27.5 | 100.6 ± 27.5 | 43.0 ± 31.2 |
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
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 CYP450 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 CYP450 mediated interactions involving tenofovir with other medicinal products is low (see Pharmacokinetics).
Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of VIREAD with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the coadministered drug, due to competition for this elimination pathway. Drugs that decrease renal function may also increase serum concentrations of tenofovir.
VIREAD has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir. Tables 3 and 4 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.
Table 5 summarizes the drug interaction between VIREAD and didanosine. When administered with multiple doses of VIREAD, the Cmax and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with VIREAD, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.
Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating lack of clinically significant drug interactions between these agents and VIREAD.
Table 5 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD | DidanosineSee PRECAUTIONS regarding use of didanosine with VIREAD. Dose (mg)/Method of Administration
| VIREAD Method of Administration | N | % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted
Increase = ↑; Decrease = ↓; No Effect = 
|
|---|
| Cmax | AUC |
|---|
| Buffered tablets | | | |
| 400 once daily Includes 4 subjects weighing <60 kg receiving ddI 250 mg. × 7 days | Fasted 1 hour after didanosine | 14 | ↑ 28
(↑ 11 to ↑ 48) | ↑ 44
(↑ 31 to ↑ 59) |
| Enteric coated capsules | | | |
| 400 once, fasted | With food, 2 hours after didanosine | 26 | ↑ 48
(↑ 25 to ↑ 76) | ↑ 48
(↑ 31 to ↑ 67) |
| 400 once, with food | Simultaneously with didanosine | 26 | ↑ 64
(↑ 41 to ↑ 89) | ↑ 60
(↑ 44 to ↑ 79) |
| 250 once, fasted | With food, 2 hours after didanosine | 28 | ↓ 10
(↓ 22 to ↑ 3) | |
| 250 once, fasted | Simultaneously with didanosine | 28 | | ↑ 14
(0 to ↑ 31) |
| 250 once, with food | Simultaneously with didanosine | 28 | ↓ 29
(↓ 39 to ↓ 18) | ↓ 11
(↓ 23 to ↑ 2) |
|
