EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE (Page 6 of 10)
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Emtricitabine and tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4)].
12.3 Pharmacokinetics
Emtricitabine and tenofovir disoproxil fumarate tablets: One emtricitabine and tenofovir disoproxil fumarate tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).
Emtricitabine
The pharmacokinetic properties of FTC are summarized in Table 8. Following oral administration of FTC, FTC is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 μg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC 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 FTC, the plasma FTC half-life is approximately 10 hours.
Tenofovir Disoproxil Fumarate
The pharmacokinetic properties of TDF are summarized in Table 8. Following oral administration of TDF, maximum tenofovir serum concentrations are achieved in 1.0 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mg/mL. Approximately 70 to 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 TDF, the terminal elimination half-life of tenofovir is approximately 17 hours.
| a. NC=Not calculated | ||
| b. Median (range) | ||
| c. Mean ( SD) | ||
| d. Data presented as steady state values | ||
| FTC | Tenofovir | |
| Fasted Oral Bioavailabilityb (%) | 92 (83.1 to 106.4) | 25 (NC to 45.0) |
| Plasma Terminal Elimination Half-Lifeb (hr) | 10 (7.4 to 18.0) | 17 (12.0 to 25.7) |
| Cmax c (µg/mL) | 1.8 ± 0.72d | 0.30 ± 0.09 |
| AUCc (µg-hr/mL) | 10.0 ± 3.12d | 2.29 ± 0.69 |
| CL/Fc (mL/min) | 302 ± 94 | 1043 ± 115 |
| CLrenal c (mL/min) | 213 ± 89 | 243 ± 33 |
Effects of Food on Oral Absorption
Emtricitabine and tenofovir disoproxil fumarate tablets may be administered with or without food. Administration of emtricitabine and tenofovir disoproxil fumarate tablets 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 trials, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and Cmax ) were unaffected when emtricitabine and tenofovir disoproxil fumarate tablets was administered with either a high fat or a light meal.
Specific Populations
Race:
Emtricitabine
No pharmacokinetic differences due to race have been identified following the administration of FTC.
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 TDF.
Gender:
Emtricitabine and Tenofovir Disoproxil Fumarate
FTC and tenofovir pharmacokinetics are similar in male and female subjects.
Pediatric Patients:
Treatment of HIV-1 Infection
The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate tablets in pediatric subjects weighing 17 kg and above are not available. The dosage recommendations of emtricitabine and tenofovir disoproxil fumarate tablets in this population are based on the dosage recommendations of FTC and TDF in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients.
HIV-1 PrEP
The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate tablets in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.
Geriatric Patients:
Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older).
Patients with Renal Impairment:
The pharmacokinetics of FTC and tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax and AUC0- of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment.
Patients with Hepatic Impairment:
The pharmacokinetics of tenofovir following a 300 mg dose of TDF 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. The pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate tablets or FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Assessment of Drug Interactions:
The steady state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone.
In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low.
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 FTC and famciclovir, indinavir, stavudine, TDF, and zidovudine (Tables 9 and 10). Similarly, no clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 11 and 12).
| a. All interaction trials conducted in healthy volunteers | ||||||
| b. ↑= Increase; ⇔ = No Effect; NA = Not Applicable | ||||||
| Coadministered Drug | Dose of Coadministered Drug (mg) | FTC Dose (mg) | N | % Change of FTC Pharmacokinetic Parametersb (90% CI) | ||
| C max | A U C | C min | ||||
| TDF | 300 once daily x 7 days | 200 once daily 7 days | 17 | ⇔ | ⇔ | ↑20 ↑12 to↑29 |
| Zidovudine | 300 twice daily x 7 days | 200 once daily 7 days | 27 | ⇔ | ⇔ | ⇔ |
| Indinavir | 800 1 | 200 1 | 12 | ⇔ | ⇔ | NA |
| Famciclovir | 500 1 | 200 1 | 12 | ⇔ | ⇔ | NA |
| Stavudine | 40 1 | 200 1 | 6 | ⇔ | ⇔ | NA |
| a. All interaction trials conducted in healthy volunteers | ||||||
| b. ↑= Increase; ⇔ = No Effect; NA = Not Applicable | ||||||
| Coadministered Drug | Dose of Coadministered Drug (mg) | FTC Dose (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parametersb (90% CI) | ||
| C max | A U C | C min | ||||
| TDF | 300 once daily 7 days | 200 once daily 7 days | 17 | ⇔ | ⇔ | ⇔ |
| Zidovudine | 300 twice daily 7 days | 200 once daily 7 days | 27 | ↑17 ( ↑0 to ↑38) | ↑13 ( ↑5 to ↑20) | ⇔ |
| Indinavir | 800 1 | 200 1 | 12 | ⇔ | ⇔ | NA |
| Famciclovir | 500 1 | 200 1 | 12 | ⇔ | ⇔ | NA |
| Stavudine | 40 1 | 200 1 | 6 | ⇔ | ⇔ | NA |
| a. Subjects received VIREAD 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 (efavirenz/FTC/TDF) coadministered with HARVONI. | |||||
| i. Study conducted with COMPLERA (FTC/rilpivirine/TDF) coadministered with HARVONI. | |||||
| j. Study conducted with emtricitabine and tenofovir disoproxil fumarate tablets (FTC/TDF) + dolutegravir coadministered with HARVONI. | |||||
| k. Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir). | |||||
| l. 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, emtricitabine and tenofovir disoproxil fumarate tablets + atazanavir/ritonavir, or emtricitabine and tenofovir disoproxil fumarate tablets + darunavir/ritonavir. | |||||
| m. Administered as raltegravir + FTC/TDF. | |||||
| n. Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. | |||||
| o. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients | |||||
| p. Aptivus Prescribing Information. | |||||
| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Tenofovir Pharmacokinetic Parametersb (90% CI) | ||
| C max | A U C | C min | |||
| Atazanavirc | 400 once daily 14 days | 33 | ↑ 14 (↑ to ↑20) | ↑ 24 (↑ 21 to ↑ 28) | ↑ 22 (↑ 15 to ↑ 30) |
| Atazanavir/ Ritonavirc | 300/100 once daily | 12 | ↑ 34 (↑ 20 to ↑ 51) | 37 (↑ 30 to ↑ 45) | ↑ 29 (↑ 21 to ↑ 36) |
| Darunavir/ Ritonavird | 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/ Sofosbuvire,f | 90/400 once daily 10 days | 24 | ↑ 47 (↑ 37 to ↑ 58) | ↑ 35 (↑ 29 to ↑42 ) | ↑ 47 (↑ 38 to ↑ 57) |
| Ledipasvir/ Sofosbuvire,g | 23 | ↑ 64 (↑ 54 to ↑ 74) | ↑ 50 (↑ 42 to ↑ 59) | ↑ 59 (↑ 49 to ↑ 70) | |
| Ledipasvir/ Sofosbuvirh | 90/400 once daily 14 days | 15 | ↑ 79 (↑ 56 to ↑ 104) | ↑ 98 (↑ 77 to ↑ 123) | ↑ 163 (↑ 132 to ↑ 197) |
| Ledipasvir/ Sofosbuviri | 90/400 once daily 10 days | 14 | ↑ 32 (↑ 25 to ↑ 39 ) | ↑ 40 (↑ 31 to ↑ 50 ) | ↑ 91 (↑ 74 to ↑ 110) |
| Ledipasvir/ Sofosbuvirj | 90/400 once daily 10 days | 29 | ↑ 61 (↑ 51 to ↑ 72) | ↑ 65 (↑ 59 to ↑ 71) | ↑ 115 (↑ 105 to ↑ 126) |
| 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) |
| Sofosbuvirk | 400 single dose | 16 | ↑ 25 (↑ 8 to ↑ 45) | ⇔ | ⇔ |
| Sofosbuvir/ Velpatasvirl | 400/100 once daily | 24 | ↑ 44 (↑ 33 to ↑ 55) | ↑ 40 (↑ 34 to ↑ 46) | ↑ 84 (↑ 76 to ↑ 92) |
| Sofosbuvir/ Velpatasvirm | 400/100 once daily | 30 | ↑ 46 (↑ 39 to ↑ 54) | ↑ 40 (↑ 34 to ↑ 45) | ↑ 70 (↑ 61 to ↑ 79) |
| Sofosbuvir/ Velpatasvir/ Voxilaprevirn | 400/100/100 + Voxilapreviro 100 once daily | 29 | ↑ 48 (↑ 36 to ↑ 61) | ↑ 39 (↑ 32 to ↑ 46) | ↑ 47 (↑ 38 to ↑ 56) |
| Tacrolimus | 0.05 mg/kg twice daily 7 days | 21 | ↑ 13 (↑ 1 to ↑ 27) | ⇔ | ⇔ |
| Tipranavir/ Ritonavirp | 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 emtricitabine and tenofovir disoproxil fumarate tablets: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine.
| a. Increase = ↑; Decrease = ↓; No Effect = ⇔ ; NA = Not Applicable | |||||
| b. Reyataz Prescribing Information. | |||||
| c. In HIV-infected subjects, addition of TDF 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. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric coated capsules alone under fasted conditions. | |||||
| 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 TDF and ritonavir-boosted saquinavir are coadministered. | |||||
| i. Aptivus Prescribing Information. | |||||
| Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI) | ||
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↑12 (↓1 to ↑26) | ⇔ | NA |
| Atazanavirb | 400 once daily x 14 days | 34 | ↓21 (↓27 to ↓14) | ↓25 (↓ 30 to ↓ 19) | ↓40 (↓48 to ↓32) |
| Atazanavirb | Atazanavir/Ritonavir 300/100 once daily x 42 days | 10 | ↓ 28 (↓ 50 to ↑ 5) | ↓ 25C (↓ 42 to ↓ 3) | ↓ 23C (↓ 46 to ↑ 10) |
| Darunavird | Darunavir/Ritonavir 300/100 mg once daily | 12 | ↑ 16 (↓ 6 to ↑ 42) | ↑ 21 (↓ 5 to ↑ 54) | ↑ 24 (↓ 10 to ↑ 69) |
| Didanosinee | 250 once, simultaneously with TDF and a light mealf | 33 | ↓ 20g (↓ 32 to ↓ 7) | ⇔g | NA |
| Emtricitabine | 200 once daily x 7 days | 17 | ⇔ | ⇔ | ↑20 (↑ 12 to ↑ 29) |
| Indinavir | 800 three times daily x 7 days | 12 | ↓11 (↓30 to ↑ 12) | ⇔ | ⇔ |
| Entecavir | 1 once daily x 10 days | 28 | ⇔ | ↑13 (↑11 to ↑15) | ⇔ |
| Lamivudine | 150 twice daily x 7 days | 15 | ↓24 (↓34 to ↓12) | ⇔ | ⇔ |
| Lopinavir Ritonavir | Lopinavir/Ritonavir 400/100 twice daily x 14 days | 24 | ⇔ ⇔ | ⇔ ⇔ | ⇔ ⇔ |
| Saquinavir Ritonavir | Saquinavir/Ritonavir 1000/100 twice daily × 14 days | 32 | ↑ 22 (↑ 6 to ↑41) ⇔ | ↑ 29h (↑ 12 to ↑ 48) ⇔ | ↑ 47h (↑ 23 to ↑ 76) ↑ 23 (↑ 3 to ↑ 46) |
| Tacrolimus | 0.05 mg/kg twice daily x 7 days | 21 | ⇔ | ⇔ | ⇔ |
| Tipranaviri | 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) | |
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