Truvada (Page 6 of 10)
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
TRUVADA is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4)].
12.3 Pharmacokinetics
TRUVADA: One TRUVADA 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 1–2 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 0.02–200 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 0.01–25 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 TDF, the terminal elimination half-life of tenofovir is approximately 17 hours.
FTC | 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 trials, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and Cmax ) were unaffected when TRUVADA 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 TRUVADA in pediatric subjects weighing 17 kg and above are not available. The dosage recommendations of TRUVADA 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 TRUVADA in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of TRUVADA 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 TRUVADA 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).
Coadministered Drug | Dose of Coadministered Drug (mg) | FTC Dose (mg) | N | % Change of FTC Pharmacokinetic Parameters † (90% CI) | ||
---|---|---|---|---|---|---|
Cmax | AUC | Cmin | ||||
TDF | 300 once daily × 7 days | 200 once daily × 7 days | 17 | ⇔ | ⇔ | ↑ 20(↑ 12 to ↑ 29) |
Zidovudine | 300 twice daily × 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 |
Coadministered Drug | Dose of Coadministered Drug (mg) | FTC Dose (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters † (90% CI) | ||
---|---|---|---|---|---|---|
Cmax | AUC | Cmin | ||||
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 |
Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Tenofovir Pharmacokinetic Parameters †(90% CI) | ||
---|---|---|---|---|---|
Cmax | AUC | Cmin | |||
| |||||
Atazanavir ‡ | 400 once daily × 14 days | 33 | ↑ 14(↑ 8 to ↑ 20) | ↑ 24(↑ 21 to ↑ 28) | ↑ 22(↑ 15 to ↑ 30) |
Atazanavir/ Ritonavir ‡ | 300/100 once daily | 12 | ↑ 34(↑ 20 to ↑ 51) | ↑ 37(↑ 30 to ↑ 45) | ↑ 29(↑ 21 to ↑ 36) |
Darunavir/ Ritonavir § | 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 ¶, # | 90/400 once daily × 10 days | 24 | ↑ 47(↑ 37 to ↑ 58) | ↑ 35(↑ 29 to ↑42 ) | ↑ 47(↑ 38 to ↑ 57) |
Ledipasvir/ Sofosbuvir ¶, Þ | 23 | ↑ 64(↑ 54 to ↑ 74) | ↑ 50(↑ 42 to ↑ 59) | ↑ 59(↑ 49 to ↑ 70) | |
Ledipasvir/ Sofosbuvir ß | 90/400 once daily × 14 days | 15 | ↑ 79(↑ 56 to ↑ 104) | ↑ 98(↑ 77 to ↑ 123) | ↑ 163(↑ 132 to ↑ 197) |
Ledipasvir/ Sofosbuvir à | 90/400 once daily × 10 days | 14 | ↑ 32(↑ 25 to ↑ 39 ) | ↑ 40(↑ 31 to ↑ 50 ) | ↑ 91(↑ 74 to ↑ 110) |
Ledipasvir/ Sofosbuvir è | 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) |
Sofosbuvir ð | 400 single dose | 16 | ↑ 25(↑ 8 to ↑ 45) | ⇔ | ⇔ |
Sofosbuvir/ Velpatasvir ø | 400/100 once daily | 24 | ↑ 44(↑ 33 to ↑ 55) | ↑ 40(↑ 34 to ↑ 46) | ↑ 84(↑ 76 to ↑ 92) |
Sofosbuvir/ Velpatasvir ý | 400/100 once daily | 30 | ↑ 46(↑ 39 to ↑ 54) | ↑ 40(↑ 34 to ↑ 45) | ↑ 70(↑ 61 to ↑ 79) |
Sofosbuvir/ Velpatasvir/Voxilaprevir £ | 400/100/100 + Voxilaprevir ¥ 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/ Ritonavir Œ | 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 TRUVADA: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine.
Coadministered Drug | Dose of Coadministered Drug (mg) | N | % Change of Coadministered Drug Pharmacokinetic Parameters * (90% CI) | ||
---|---|---|---|---|---|
Cmax | AUC | Cmin | |||
| |||||
Abacavir | 300 once | 8 | ↑ 12(↓ 1 to ↑ 26) | ⇔ | NA |
Atazanavir † | 400 once daily × 14 days | 34 | ↓ 21(↓ 27 to ↓ 14) | ↓ 25(↓ 30 to ↓ 19) | ↓ 40(↓ 48 to ↓ 32) |
Atazanavir † | Atazanavir/Ritonavir 300/100 once daily × 42 days | 10 | ↓ 28(↓ 50 to ↑ 5) | ↓ 25‡(↓ 42 to ↓ 3) | ↓ 23‡(↓ 46 to ↑ 10) |
Darunavir § | Darunavir/Ritonavir 300/100 once daily | 12 | ↑ 16(↓ 6 to ↑ 42) | ↑ 21(↓ 5 to ↑ 54) | ↑ 24(↓ 10 to ↑ 69) |
Didanosine ¶ | 250 once, simultaneously with TDF and a light meal # | 33 | ↓ 20Þ(↓ 32 to ↓ 7) | ⇔Þ | NA |
Emtricitabine | 200 once daily × 7 days | 17 | ⇔ | ⇔ | ↑ 20(↑ 12 to ↑ 29) |
Indinavir | 800 three times daily × 7 days | 12 | ↓ 11(↓ 30 to ↑ 12) | ⇔ | ⇔ |
Entecavir | 1 once daily × 10 days | 28 | ⇔ | ↑ 13(↑ 11 to ↑ 15) | ⇔ |
Lamivudine | 150 twice daily × 7 days | 15 | ↓ 24(↓ 34 to ↓ 12) | ⇔ | ⇔ |
Lopinavir | Lopinavir/Ritonavir 400/100 twice daily × 14 days | 24 | ⇔ | ⇔ | ⇔ |
Ritonavir | ⇔ | ⇔ | ⇔ | ||
Saquinavir | Saquinavir/Ritonavir 1000/100 twice daily × 14 days | 32 | ↑ 22(↑ 6 to ↑41) | ↑ 29ß(↑ 12 to ↑ 48) | ↑ 47ß(↑ 23 to ↑ 76) |
Ritonavir | ⇔ | ⇔ | ↑ 23(↑ 3 to ↑ 46) | ||
Tacrolimus | 0.05 mg/kg twice daily × 7 days | 21 | ⇔ | ⇔ | ⇔ |
Tipranavir à | 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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