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.
Rilpivirine | Emtricitabine | Tenofovir Alafenamide | |
---|---|---|---|
PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1. | |||
| |||
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 |
ParameterMean (CV%) | Emtricitabine * | Rilpivirine † | Tenofovir Alafenamide ‡ | Tenofovir § |
---|---|---|---|---|
CV = Coefficient of Variation; NA = Not Applicable | ||||
| ||||
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).
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)¶ |
| ||||
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.
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).
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 | ||||||
| ||||||
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) |
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 | ||||||
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 |
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 | ||||||
| ||||||
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) |
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 | ||||||
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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