ODEFSEY (Page 6 of 10)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ODEFSEY is a fixed dose combination of antiretroviral drugs emtricitabine, rilpivirine, and tenofovir alafenamide [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

When higher than recommended RPV doses of 75 mg (3 times the recommended dosage in ODEFSEY) once daily and 300 mg (12 times the recommended dosage in ODEFSEY) once daily were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6 times and 6.7 times, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.6)].

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2 (5) milliseconds (i.e., below the threshold of clinical concern).

In a thorough QT/QTc study in 48 healthy subjects, TAF at the recommended dose and at a dose approximately 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval.

The effect of FTC on the QT interval is not known.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of the components of ODEFSEY are provided in Table 4. The multiple dose pharmacokinetic parameters of FTC, RPV and TAF and its metabolite tenofovir are provided in Table 5.

Table 4 Pharmacokinetic Properties of the Components of ODEFSEY
Rilpivirine Emtricitabine Tenofovir Alafenamide
PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1.
*
Values refer to geometric mean ratio [fed/ fasted] in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~800 kcal, 50% fat. Moderate-fat meal = ~600 kcal, 27% fat.
In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.
t1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs.
§
Dosing in mass balance studies: FTC (single dose administration of [14 C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14 C] tenofovir alafenamide).
Absorption
Tmax (h) 4 3 1
Effect of moderate fat meal (relative to fasting)* AUC Ratio = 1.13 (1.03, 1.23) AUC Ratio = 0.91 (0.89, 0.93) AUC Ratio = 1.45(1.33, 1.58)
Effect of high fat meal (relative to fasting)* AUC Ratio = 1.72 (1.49, 1.99) AUC Ratio = 0.88 (0.85, 0.90) AUC Ratio = 1.53(1.39, 1.69)
Distribution
% Bound to human plasma proteins ~99 <4 ~80
Source of protein binding data In vitro In vitro Ex vivo
Blood-to-plasma ratio 0.7 0.6 1.0
Metabolism
Metabolism CYP3A Not significantly metabolized Cathepsin A (PBMCs)CES1 (hepatocytes)CYP3A (minimal)
Elimination
Major route of elimination Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose)
t1/2 (h) 50 10 0.51
% Of dose excreted in urine § 6 70 <1
% Of dose excreted in feces § 85 13.7 31.7
Table 5 Multiple Dose Pharmacokinetic Parameters of Emtricitabine, Rilpivirine, Tenofovir Alafenamide and its Metabolite Tenofovir Following Oral Administration with a Meal in HIV-Infected Adults
ParameterMean (CV%) Emtricitabine * Rilpivirine Tenofovir Alafenamide Tenofovir §
CV = Coefficient of Variation; NA = Not Applicable
*
From Intensive PK analysis in a phase 2 trial in HIV infected adults treated with FTC+TAF with EVG+COBI (n=19).
From Population PK analysis in a trial of treatment-naïve adults with HIV-1 infection treated with RPV (n=679).
From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated within EVG+COBI+FTC+TAF (n=539).
§
From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection treated with EVG+COBI+FTC+TAF (n=841).
Cmax (microgram per mL) 2.1 (20.2) NA 0.16 (51.1) 0.02 (26.1)
AUCtau (microgram∙hour per mL) 11.7 (16.6) 2.2 (38.1) 0.21 (71.8) 0.29 (27.4)
Ctrough (microgram per mL) 0.10 (46.7) 0.08 (44.3) NA 0.01 (28.5)

Specific Populations

Geriatric Patients

The pharmacokinetics of FTC and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of FTC+TAF with EVG+COBI showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

The pharmacokinetics of RPV have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)].

Pediatric Patients

Exposures of TAF in 24 pediatric subjects with HIV-1 infection aged 12 to less than 18 years who received FTC+TAF with EVG+COBI were decreased (23% for TAF AUC) compared to exposures achieved in treatment-naïve adults following administration of FTC+TAF with EVG+COBI. These exposure differences are not thought to be clinically significant based on exposure-response relationships. FTC exposures were similar in adolescents compared to treatment-naïve adults. The PK of RPV in antiretroviral HIV-1-infected pediatric subjects 12 to less than 18 years of age who received RPV 25 mg once daily were comparable to those in HIV-1 infected adults. As in adults, there was no impact of body weight on RPV PK in pediatric subjects [see Use In Specific Populations (8.4)].

Race and Gender

No clinically significant changes in the pharmacokinetics of the components of ODEFSEY have been observed based on race or gender.

Patients with Renal Impairment

Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1 infected subjects with eGFR 60 to 89 mL per minute by Cockcroft-Gault method relative to HIV-1 infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease [see Use in Specific Populations (8.6)].

Emtricitabine and Tenofovir Alafenamide: The pharmacokinetics of FTC+TAF with EVG+COBI in HIV-1 infected subjects with renal impairment (eGFR 30 to 69 mL per minute by Cockcroft-Gault method), and in HIV-1 infected subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically-suppressed subjects in open-label trials. The pharmacokinetics of TAF were similar among healthy subjects, subjects with mild or moderate renal impairment, and subjects with ESRD receiving chronic hemodialysis; increases in FTC and TFV exposures in subjects with renal impairment were not considered clinically relevant (Table 6).

Table 6 Pharmacokinetics of FTC and a Metabolite of TAF (Tenofovir) in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function
AUCtau (microgram-hour per mL)Mean (CV%)
Estimated Creatinine Clearance * ≥90 mL per minute (N=18) 60–89 mL per minute (N=11) 30–59 mL per minute (N=18)§ <15 mL per minute (N=12)
*
By Cockcroft-Gault method.
From a phase 2 trial in HIV-infected adults with normal renal function treated with FTC+TAF with EVG+COBI.
These subjects had an eGFR ranging from 60 to 69 mL per minute.
§
From a phase 3 trial in HIV infected adults with renal impairment treated with FTC+TAF with EVG+COBI.
From a phase 3 trial in HIV infected adults with ESRD receiving chronic hemodialysis treated with FTC+TAF with EVG+COBI; PK assessed prior to hemodialysis following 3 consecutive daily doses of FTC+TAF with EVG+COBI.
#
N=11.
Þ
N=10.
Emtricitabine 11.4 (11.9) 17.6 (18.2) 23.0 (23.6) 62.9 (48.0)#
Tenofovir 0.32 (14.9) 0.46 (31.5) 0.61 (28.4) 8.72 (39.4)Þ

Patients with Hepatic Impairment

Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.

Rilpivirine: In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple-dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment [see Use in Specific Populations (8.7)].

Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in subjects with mild, moderate, (Child-Pugh A and B) or severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7)].

Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of FTC and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure of RPV.

Pregnancy and Postpartum

Rilpivirine: The exposure (C0h and AUC24h ) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 7). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.

Table 7 Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
Pharmacokinetics of total rilpivirine(mean ± SD, tmax : median [range]) Postpartum(6–12 Weeks)(n=11) 2nd Trimester of pregnancy(n=15) 3rd Trimester of pregnancy(n=13)
C0h , ng/mL 111 ± 69.2 65.0 ± 23.9 63.5 ± 26.2
Cmin , ng/mL 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4
Cmax , ng/mL 167 ± 101 121 ± 45.9 123 ± 47.5
tmax , h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93)
AUC24h , ng.h/mL 2714 ± 1535 1792 ± 711 1762 ± 662

Drug Interaction Studies

Rilpivirine: RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV.

RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

TAF is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. TAF is a weak inhibitor of CYP3A in vitro. TAF is not an inhibitor or inducer of CYP3A in vivo.

The drug interaction studies described in Tables 8–11 were conducted with ODEFSEY (FTC/RPV/TAF) or the components of ODEFSEY (FTC, RPV, or TAF) administered individually.

The effects of coadministered drugs on the exposures of RPV and TAF are shown in Tables 8 and 9, respectively. The effects of RPV and TAF on the exposure of coadministered drugs are shown in Tables 10 and 11, respectively. For information regarding clinical recommendations, see Drug Interactions (7).

Table 8 Changes in Pharmacokinetic Parameters for RPV in the Presence of Coadministered Drugs in Healthy Subjects
Coadministered Drug Dose/Schedule Mean Ratio of RPVPharmacokinetic Parameters With/Without Coadministered Drug (90% CI);No Effect = 1.00
Coadministered Drug (mg) RPV (mg) N Cmax AUC Cmin
CI=Confidence Interval; N=maximum number of subjects with data; NA=Not Available; ↔=no change
*
25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times the recommended dose of RPV in ODEFSEY, respectively.
Study conducted with RPV.
Comparison based on historic controls.
§
Study conducted with ODEFSEY (FTC/RPV/TAF).
Study conducted with FTC/RPV/TDF.
#
Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Acetaminophen 500 single dose 150 once daily * 16 1.09(1.01, 1.18) 1.16(1.10, 1.22) 1.26(1.16, 1.38)
Atorvastatin 40 once daily 150 once daily * 16 0.91(0.79, 1.06) 0.90(0.81, 0.99) 0.90(0.84, 0.96)
Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily * 16 1.17(1.08, 1.27) 1.25(1.16, 1.35) 1.18(1.09, 1.28)
Ethinylestradiol/Norethindrone 0.035 once daily /1 mg once daily 25 once daily 15
Famotidine 40 single dose taken 12 hours before RPV 150 single dose * 24 0.99(0.84, 1.16) 0.91(0.78, 1.07) NA
Famotidine 40 single dose taken 2 hours before RPV 150 single dose * 23 0.15(0.12, 0.19) 0.24(0.20, 0.28) NA
Famotidine 40 single dose taken 4 hours after RPV 150 single dose * 24 1.21(1.06, 1.39) 1.13(1.01, 1.27) NA
Ketoconazole 400 once daily 150 once daily * 15 1.30(1.13, 1.48) 1.49(1.31, 1.70) 1.76(1.57, 1.97)
Methadone 60–100 once daily, individualized dose 25 once daily 12
Ledipasvir/Sofosbuvir 90/400 once daily 25 once daily § 42 0.97(0.92, 1.02) 0.95(0.91, 0.98) 0.93(0.89, 0.97)
Omeprazole 20 once daily 25 single dose 15 0.30(0.24, 0.38) 0.35(0.28, 0.44) NA
Rifabutin 300 once daily 25 once daily 18 0.69(0.62, 0.76) 0.58(0.52, 0.65) 0.52(0.46, 0.59)
Rifampin 600 once daily 150 once daily * 16 0.31(0.27, 0.36) 0.20(0.18, 0.23) 0.11(0.10, 0.13)
Simeprevir 25 once daily 150 once daily 23 1.04(0.95, 1.30) 1.12(1.05, 1.19) 1.25(1.16, 1.35)
Sildenafil 50 single dose 75 once daily * 16 0.92(0.85, 0.99) 0.98(0.92, 1.05) 1.04(0.98, 1.09)
Sofosbuvir/velpatasvir 400/100 once daily 10 once daily 24 0.93(0.88,0.98) 0.95(0.90, 1.00) 0.96(0.90,1.03)
Sofosbuvir/velpatasvir/voxilaprevir 400/100/100 + 100 voxilaprevir # once daily 25 once daily § 30 0.79(0.74, 0.84) 0.80(0.76, 0.85) 0.82(0.77, 0.87)
Table 9 Changes in Pharmacokinetic Parameters for TAF in the Presence of the Coadministered Drug * in Healthy Subjects
Coadministered Drug Dose of Coadministered Drug (mg) TAF (mg) N Mean Ratio of Tenofovir Alafenamide Pharmacokinetic Parameters (90% CI);No Effect = 1.00
Cmax AUC Cmin
CI=Confidence Interval; N=maximum number of subjects with data; NA=Not Available
*
All interaction studies conducted in healthy volunteers.
Increases TAF exposure via inhibition of intestinal P-glycoprotein.
Study conducted with ODEFSEY (FTC/RPV/TAF).
§
Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
Cobicistat 150 once daily 8 once daily 12 2.83(2.20, 3.65) 2.65(2.29, 3.07) NA
Ledipasvir/Sofosbuvir 90/400 once daily 25 once daily 42 1.03(0.94, 1.14) 1.32(1.25, 1.40) NA
Sofosbuvir/velpatasvir/voxilaprevir 400/100/100 + 100 voxilaprevir § once daily 25 once daily 30 1.32(1.17, 1.48) 1.52(1.43,1.61) NA
Table 10 Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV in Healthy Subjects
Coadministered Drug Dose/Schedule Mean Ratio of Coadministered Drug Pharmacokinetic Parameters With/Without RPV (90% CI); No Effect = 1.00
Coadministered Drug (mg) RPV (mg) N Cmax AUC Cmin
CI=Confidence Interval; N=maximum number of subjects with data; NA=Not Available
*
25 mg, 75 mg, and 150 mg of RPV is 1, 3, and 6 times the recommended dose of RPV in ODEFSEY, respectively.
Study conducted with RPV.
AUC(0–last) .
§
Study conducted with ODEFSEY (FTC/RPV/TAF).
The predominant circulating nucleoside metabolite of sofosbuvir.
#
N (maximum number of subjects with data for AUC(0–∞) =15)
Þ
Study conducted with FTC/RPV/TDF.
Acetaminophen 500 single dose 150 once daily * 16 0.97(0.86, 1.10) 0.92(0.85, 0.99) NA
Atorvastatin 40 once daily 150 once daily * 16 1.35(1.08, 1.68) 1.04(0.97, 1.12) 0.85(0.69, 1.03)
2-hydroxy-atorvastatin 1.58(1.33, 1.87) 1.39(1.29, 1.50) 1.32(1.10, 1.58)
4-hydroxy-atorvastatin 1.28(1.15, 1.43) 1.23(1.13, 1.33) NA
Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily * 16 0.98(0.85, 1.13) 1.03(0.95, 1.13) NA
Digoxin 0.5 single dose 25 once daily 22 1.06(0.97, 1.17) 0.98(0.93, 1.04) NA
Ethinylestradiol 0.035 once daily 25 once daily 17 1.17(1.06, 1.30) 1.14(1.10, 1.19) 1.09(1.03, 1.16)
Norethindrone 1 mg once daily 0.94(0.83, 1.06) 0.89(0.84, 0.94) 0.99(0.90, 1.08)
Ketoconazole 400 once daily 150 once daily * 14 0.85(0.80, 0.90) 0.76(0.70, 0.82) 0.34(0.25, 0.46)
Ledipasvir 90 once daily 25 once daily § 41 1.01(0.97, 1.05) 1.02(0.97, 1.06) 1.02(0.98, 1.07)
Sofosbuvir 400 once daily 25 once daily § 41 0.96(0.89, 1.04) 1.05(1.01, 1.09) NA
GS-331007 1.08(1.05, 1.11) 1.08(1.06, 1.10) 1.10(1.07, 1.12)
R(-) methadone 60–100 once daily, individualized dose 25 once daily 13 0.86(0.78, 0.95) 0.84(0.74, 0.95) 0.78(0.67, 0.91)
S(+) methadone 0.87(0.78, 0.97) 0.84(0.74, 0.96) 0.79(0.67, 0.92)
Metformin 850 single dose 25 once daily 20 1.02(0.95, 1.10) 0.97(0.90,1.06)# NA
Rifampin 600 once daily 150 once daily * 16 1.02(0.93, 1.12) 0.99(0.92, 1.07) NA
25-desacetylrifampin 1.00(0.87, 1.15) 0.91(0.77, 1.07) NA
Simeprevir 150 once daily 25 once daily 21 1.10(0.97, 1.26) 1.06(0.94, 1.19) 0.96(0.83, 1.11)
Sildenafil 50 single dose 75 once daily * 16 0.93(0.80, 1.08) 0.97(0.87, 1.08) NA
N -desmethyl-sildenafil 0.90(0.80, 1.02) 0.92(0.85, 0.99) NA
SofosbuvirGS-331007 400 once daily 25 once daily Þ 24 1.09(0.95, 1.25)0.96(0.90, 1.01) 1.16(1.10, 1.24)1.04(1.00, 1.07) NA1.12(1.07, 1.17)
Velpatasvir 100 once daily 25 once daily Þ 24 0.96(0.85, 1.10) 0.99(0.88, 1.11) 1.02(0.91, 1.15)
Sofosbuvir 400 once daily 25 once daily § 30 0.95(0.86, 1.05) 1.01(0.97, 1.06) NA
GS-331007 1.02(0.98, 1.06) 1.04(1.01, 1.06) NA
Velpatasvir 100 once daily 25 once daily § 30 1.05(0.96, 1.16) 1.01(0.94, 1.07) 1.01(0.95, 1.09)
Voxilaprevir 100 + 100 once daily 25 once daily § 30 0.96(0.84, 1.11) 0.94(0.84, 1.05) 1.02(0.92, 1.12)
Table 11 Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TAF in Healthy Subjects
Coadministered Drug Dose of Coadministered Drug (mg) TAF (mg) N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin
CI=Confidence Interval; N=maximum number of subjects with data; NA=Not Available
*
A sensitive CYP3A4 substrate.
Study conducted with TAF.
Study conducted with ODEFSEY (FTC/RPV/TAF).
§
The predominant circulating nucleoside metabolite of sofosbuvir.
Study conducted with FTC/TAF.
Midazolam * 2.5 single dose, orally 25 once daily 18 1.02(0.92, 1.13) 1.13(1.04, 1.23) NA
1 single dose, IV 0.99(0.89, 1.11) 1.08(1.04, 1.13) NA
Ledipasvir 90/400 once daily 25 once daily 41 1.01(0.97, 1.05) 1.02(0.97, 1.06) 1.02(0.98,1.07)
Sofosbuvir 0.96(0.89, 1.04) 1.05(1.01, 1.09) NA
GS-331007, § 1.08(1.05, 1.11) 1.08(1.06, 1.10) 1.10 (1.07, 1.12)
Norelgestromin norgestimate 0.180/0.215/0.250 once daily/ethinyl estradiol 0.025 once daily 25 once daily 29 1.17(1.07,1.26) 1.12(1.07, 1.17) 1.16(1.08,1.24)
Norgestrel 1.10(1.02, 1.18) 1.09(1.01, 1.18) 1.11(1.03,1.20)
Ethinyl estradiol 1.22(1.15, 1.29) 1.11(1.07, 1.16) 1.02(0.93,1.12)
Sofosbuvir 400 once daily 25 once daily 30 0.95(0.86, 1.05) 1.01(0.97, 1.06) NA
GS-331007§ 1.02(0.98, 1.06) 1.04(1.01, 1.06) NA
Velpatasvir 100 once daily 1.05(0.96, 1.16) 1.01(0.94, 1.07) 1.01(0.95,1.09)
Voxilaprevir 100 + 100 once daily 0.96(0.84, 1.11) 0.94(0.84, 1.05) 1.02(0.92,1.12)

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