TENOFOVIR DISOPROXIL FUMARATE (Page 5 of 10)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [See Microbiology (12.4)].

12.3 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

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 (C max ) are achieved in 1.0 ± 0.4 hrs. C max 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 C max 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.

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 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 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC 0-∞ of approximately 40% and an increase in C max 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 C max by approximately 1 hour. C max 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.

Specific Populations

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.

Pediatric Patients

Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1 infected pediatric subjects 12 to less than 18 years of age (Table 13). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of tenofovir disoproxil fumarate 300 mg (tablet) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil fumarate 300 mg.

Table 13 Mean (± SD) Tenofovir Pharmacokinetic Parameters for H0049V-1 infected Pediatric Patients 12 years and older for the Tablet

Dose and Formulation 300 mg Tablet
12 to <18 Years (N=8)
C max (μg/mL) 0.38 ± 0.13
AUC tau (μg hr/mL) 3.39 ± 1.22

Tenofovir exposures in HBV-infected pediatric subjects (12 years to less than 18 years of age) receiving oral once-daily doses of tenofovir disoproxil fumarate 300 mg tablet were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses.

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 Warnings and Precautions (5.2)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, C max , and AUC 0-∞ of tenofovir were increased (Table 14).

Table 14 Pharmacokinetic Parameters (Mean ± SD) of Tenofovir a in Subjects with Varying Degrees of Renal Function

a 300 mg, single dose of tenofovir disoproxil fumarate

Baseline Creatinine Clearance (mL/min) >80 (N=3) 50–80 (N=10) 30–49 (N=8) 12–29 (N=11)
C max (µg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC 0-∞ (µg · hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22
CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1
CL renal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2

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 15 and 16 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.

Table 15 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a in the Presence of the Coadministered Drug

a. Subjects received tenofovir disoproxil fumarate 300 mg once daily.

b. Increase =↑; Decrease = ↓; No Effect ↔

c. Reyataz Prescribing Information.

d. Prezista Prescribing Information.

e. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results.

f. Comparison based on exposures when administered as atazanavir/ritonavir + FTC/TDF.

g. Comparison based on exposures when administered as darunavir/ritonavir + FTC/TDF.

h. Study conducted with ATRIPLA® (EFV/FTC/TDF) coadministered with HARVONI; coadministration with HARVONI also results in comparable increases in tenofovir exposure when TDF is administered as COMPLERA® (FTC/rilpivirine/TDF), or TRUVADA + dolutegravir.

i. Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).

j. Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD® (elvitegravir/cobicistat/FTC/TDF), TRUVADA

+ atazanavir/ritonavir, or TRUVADA + darunavir/ritonavir.

k. Administered as raltegravir + FTC/TDF.

l. Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF.

m. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

n. Aptivus Prescribing Information.

Coadministered Drug Dose of Coadministere d Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b (90% CI)
C max AUC C min
Atazanavir c 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30)
Atazanavir/ Ritonavir c 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36)
Darunavir/Ritonavir d 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57)
Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33)
Ledipasvir/ Sofosbuvir e,f 90/400 once daily x 10 days 24 ↑ 47 (↑ 37 to ↑ 58) ↑ 35 (↑ 29 to ↑ 42 ) ↑ 47 (↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvir e,g 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvir h 90/400 once daily x 14 days 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to↑197)
Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66)
Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23 (↑ 16 to ↑ 30)
Sofosbuvir j 400 single dose 16 ↑ 25 (↑ 8 to ↑ 45)
Sofosbuvir/ Velpatasvirj 400/100 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvirk 400/100 once daily 30 ↑ 46 (↑ 39 to ↑54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79)
Sofosbuvir/ Velpatasvir/ Voxilaprevirl 400/100/100 + Voxilaprevirm 100 once daily 29 ↑ 48 (↑ 36 to ↑ 61) ↑ 39 (↑ 32 to ↑ 46) ↑ 47 (↑ 38 to ↑ 56)
Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ↑ 13 (↑ 1 to ↑ 27)
Tipranavir/ Ritonavir n 500/100 twice daily 22 ↓ 23 (↓ 32 to ↓ 13) ↓ 2 (↓ 9 to ↑ 5) ↑ 7 (↓ 2 to ↑ 17)
750/200 twice daily (23 doses) 20 ↓ 38 (↓ 46 to ↓ 29) ↑ 2 (↓ 6 to ↑ 10) ↑ 14 (↑ 1 to ↑ 27)

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.

Table 16 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate

a Increase = ↑ ; Decrease = ↓ ; No Effect = ↔ ; NA = Not Applicable

b Reyataz Prescribing Information

c In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.

d Prezista Prescribing Information.

e Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules.

f 373 kcal, 8.2 g fat

g Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions.

h Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.

i Aptivus Prescribing Information.

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters a (90% Cl)
C max AUC C min
Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) NA
Atazanavir b 400 once daily × 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32)
Atazanavir b Atazanavir/ Ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 c (↓ 42 to ↓ 3) ↓ 23 c (↓ 46 to ↑ 10)
Darunavir d Darunavir/Ritonavir 300/100 mg once daily 12 ↑ 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69)
Didanosine e 250 once, simultaneously with tenofovir disoproxil fumarate and a light meal f 33 ↓ 20 g (↓32 to ↓7) g NA
Emtricitabine 200 once daily × 7 days 17 ↑ 20 (↑ 12 to ↑ 29)
Entecavir 1 mg once daily x 10 days 28 ↑ 13 (↑ 11 to ↑ 15)
Indinavir 800 three times daily × 7 days 12 ↓ 11 (↓ 30 to ↑ 12)
Lamivudine 150 twice daily × 7 days 15 ↓ 24 (↓ 34 to ↓ 12)
Lopinavir Ritonavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 ↔ ↔ ↔ ↔ ↔ ↔
Saquinavir Ritonavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑ 41) ↔ ↑ 29 h (↑ 12 to ↑ 48) ↔ ↑ 47 h (↑ 23 to ↑ 76) ↑ 23 (↑ 3 to ↑ 46)
Tacrolimus 0.05 mg/kg twice daily x 7 days 21
Tipranavir i Tipranavir/Ritonavir 500/100 twice daily 22 ↓ 17 (↓ 26 to ↓ 6) ↓ 18 (↓ 25 to ↓ 9) ↓ 21 (↓ 30 to ↓ 10)
Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 ↓ 11 (↓ 16 to ↓ 4) ↓ 9 (↓ 15 to ↓ 3) ↓ 12 (↓ 22 to 0)

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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