CLINICAL PHARMACOLOGY
Pharmacokinetics in Adults
TRUVADA
One TRUVADA Tablet was bioequivalent to one EMTRIVA Capsule (200 mg) plus one VIREAD Tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).
Emtricitabine
The pharmacokinetic properties of emtricitabine are summarized in Table 1. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.
Tenofovir disoproxil fumarate
The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 1. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.
Table 1 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in AdultsNC = Not calculated | | Emtricitabine | Tenofovir |
|---|
| Fasted Oral Bioavailability
(%) | 92 (83.1–106.4) | 25 (NC–45.0) |
Plasma Terminal Elimination
Half-Life (hr) | 10 (7.4–18.0) | 17 (12.0–25.7) |
| Cmax
(µg/mL) | 1.8 ± 0.72
| 0.30 ± 0.09 |
| AUC (µg∙hr/mL) | 10.0 ± 3.12 | 2.29 ± 0.69 |
| CL/F (mL/min) | 302 ± 94 | 1043 ± 115 |
| CLrenal (mL/min) | 213 ± 89 | 243 ± 33 |
Effects of Food on Oral Absorption
TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy studies, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.
Special Populations
Race
Emtricitabine
No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.
Tenofovir disoproxil fumarate
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.
Gender
Emtricitabine and tenofovir disoproxil fumarate
Emtricitabine and tenofovir pharmacokinetics are similar in male and female patients.
Pediatric and Geriatric Patients
Pharmacokinetic studies of tenofovir have not been performed in pediatric patients (<18 years). Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years) (see PRECAUTIONS, Pediatric Use, Geriatric Use).
Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal impairment (see WARNINGS, Renal Impairment). In patients with creatinine clearance <50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis (see DOSAGE AND ADMINISTRATION).
Patients with Hepatic Impairment
The pharmacokinetics of tenofovir following a 300 mg 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. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Pregnancy
(see PRECAUTIONS, Pregnancy)
Nursing Mothers
(see PRECAUTIONS, Nursing Mothers)
Drug Interactions
(see PRECAUTIONS, Drug Interactions)
TRUVADA
No drug interaction studies have been conducted using TRUVADA Tablets.
Emtricitabine and tenofovir disoproxil fumarate
The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 2 and 3). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, adefovir dipivoxil, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir in studies conducted in healthy volunteers (see Tables 4 and 5).
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.
Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 6 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown.
Table 6 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 dailyIncludes 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) |
|
