Symtuza (Page 6 of 10)

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SYMTUZA is a fixed-dose combination of antiretroviral drugs darunavir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

Thorough QT trials have been conducted for darunavir, cobicistat, and tenofovir alafenamide. The effect of emtricitabine or the combination regimen SYMTUZA on the QT interval has not been evaluated.

Darunavir: In a thorough QT/QTc study in 40 healthy subjects, darunavir doses (co-administered with 100 mg ritonavir) of approximately 2 times the recommended darunavir dose did not affect the QT/QTc interval.

Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in SYMTUZA) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the SYMTUZA fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with SYMTUZA will result in clinically relevant PR prolongation.

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

Effects on Serum Creatinine

The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFRCG ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFRCG 50–79 mL/min, N=18). A statistically significant decrease from baseline in the estimated glomerular filtration rate calculated by Cockcroft-Gault method (eGFRCG ) was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline during treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG , without affecting the actual glomerular filtration rate.

12.3 Pharmacokinetics

Absorption, Distribution, Metabolism, and Excretion

The bioavailability of the components of SYMTUZA was not affected when administered orally as a split tablet compared to administration as a tablet swallowed whole.

Pharmacokinetic (PK) properties and PK parameters of the components of SYMTUZA are provided in Table 5 and Table 6, respectively.

Table 5: Pharmacokinetic Properties of the Components of SYMTUZA
Darunavir Cobicistat Emtricitabine TAF
PBMCs = peripheral blood mononuclear cells; CES-1 = carboxylesterase-1
*
Approximately 928 kcal; 504 kcal from fat (56 g), 260 kcal from carbohydrates, and 164 kcal from protein.
Primarily alpha-1-acid glycoprotein
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 co-administration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected.
§
Note that the pharmacologically active metabolite tenofovir diphosphate has a half-life of 150–180 hours within PBMCs. Tenofovir in plasma has a median elimination half-life of approximately 44 hours.
Dosing in mass balance studies: darunavir (single dose administration of [14 C] darunavir co-administered with multiple dose ritonavir 100 mg); cobicistat (single dose administration of [14 C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [14 C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14 C] TAF).
#
Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively.
Absorption
Tmax (h) 3.0 3.0 1.5 0.5
Effect of high-fat meal * (compared to fasting)
AUClast LS mean ratio, 90% CI 1.52 (1.32–1.76) 1.41 (1.02–1.96) 1.00 (0.96–1.04) 1.12 (1.01–1.23)
Cmax LS mean ratio, 90% CI 1.82 (1.55–2.14) 1.30 (0.94–1.80) 0.79 (0.71–0.89) 0.55 (0.42–0.71)
Distribution
% bound to human plasma proteins 95 97–98 <4 ~80
Source of protein binding data In vitro In vitro In vitro Ex vivo
Blood-to-plasma ratio 0.64 0.5 0.6 1.0
Metabolism
Metabolism CYP3A CYP3A (major)CYP2D6 (minor) Not significantly metabolized Cathepsin A (PBMCs)CES1 (hepatocytes)CYP3A (minimal)
Elimination
t1/2 (h) 9.4 3.2 7.5 0.5§
Major route of elimination Metabolism Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose)
% of dose excreted in feces 79.5# 86.2 13.7 31.7
% of dose excreted in urine 13.9# 8.2 70 <1
Table 6: Steady State Pharmacokinetic Parameters of Darunavir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of SYMTUZA with Food in HIV-Infected Adults
ParameterMean (SD) Darunavir Cobicistat * Emtricitabine * TAF Tenofovir *
*
From Phase 2 PK substudy (N=21)
From population PK analysis in SYMTUZA Phase 3 study TMC114FD2HTX3001 in ARV naïve subjects (N=355)
From population PK analysis in SYMTUZA Phase 3 study TMC114IFD3013 in ARV experienced subjects (N=750)
Cmax , ng/mL 8826 (33.3)* 1129 (35.3) 2056 (25.3) 163 (51.9) * 18.8 (37.6)
AUC24h , ng.h/mL 87909 (20232) 85972 (22413) 8745 (43.9) 11918.0 (35.9) 132 (41) 339 (37.1)
C0h , ng/mL 1899 (759) 1813 (859) 31 (135) 93.1 (58.3) NA 11.7 (39.3)

Specific Populations

Geriatric Patients

Darunavir: Pharmacokinetic analysis in HIV-infected subjects taking darunavir co-administered with cobicistat, emtricitabine, and tenofovir alafenamide showed no considerable differences in darunavir pharmacokinetics for ages below or equal to 65 years compared to ages greater than 65 years (N=25).

Cobicistat and Emtricitabine: The pharmacokinetics of cobicistat and emtricitabine have not been fully evaluated in the elderly (65 years of age and older).

Tenofovir alafenamide Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of TAF combined with emtricitabine, elvitegravir, and cobicistat showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.

Pediatric Patients Weighing at Least 40 kg

Available pharmacokinetic data for the different components of SYMTUZA indicate that there were no clinically relevant differences in exposure between adults and pediatric subjects weighing at least 40 kg.

Darunavir and cobicistat: In pediatric subjects aged 12 to less than 18 years, weighing at least 40 kg who received darunavir 800 mg co-administered with cobicistat 150 mg (N=7), geometric mean darunavir Cmax values were similar between adults and pediatric subjects. Geometric mean darunavir AUC24h and C24h values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in pediatric subjects relative to adults, respectively. These differences were not considered clinically significant. Geometric mean cobicistat AUC24h , Cmax , and C24h values were comparable in pediatric subjects and adults (Table 7).

Table 7: Multiple-Dose PK Parameters of Darunavir and Cobicistat Following Administration of Darunavir with Cobicistat in HIV 1 Infected Adults and Pediatric Subjects Weighing at least 40 kg *
Parameter Geometric mean (CV%) Darunavir Cobicistat
CV = Coefficient of Variation; mcg = microgram
*
From intensive PK analysis of trial GS-US-216-0128, where HIV-infected subjects were administered darunavir 800 mg and cobicistat 150 mg once daily with 2 NRTIs
N=5; Data from two subjects who had undetectable cobicistat C24h concentrations were excluded from summary statistics
From intensive PK analysis of trial GS-US-299-0102 where HIV-infected subjects were administered SYMTUZA once daily
§
N=18
Pediatric Subjects * N=7 N=7
AUC24h (mcg.hr/mL) 77.22 (29.5) 8.33 (34.9)
Cmax (mcg/mL) 7.32 (21.7) 1.10 (20.0)
C24h (mcg/mL) 0.68 (91.6) 0.02 (123.9)
Adults N=21 N=21
AUC24h (mcg.hr/mL) 90.56 (45.3) 7.69 (43.9)
Cmax (mcg/mL) 8.34 (33.3) 1.04 (35.3)
C24h (mcg/mL) 1.00 (108.0) 0.02 (135.1)§

Emtricitabine and tenofovir alafenamide: In 24 pediatric subjects aged 12 to less than 18 years, who received emtricitabine + TAF with elvitegravir + cobicistat, geometric mean emtricitabine Cmax , and C24h values were comparable to adults, with geometric mean ratios of 1.10 (90% CI: 0.98, 1.23) and 1.07 (90% CI: 0.88, 1.29), respectively (Table 8). Geometric mean emtricitabine AUC24h was 21% higher, with a geometric mean ratio of 1.21 (90% CI: 1.09, 1.34) in pediatric subjects relative to adults. Geometric mean tenofovir alafenamide Cmax and AUClast values were 29% and 23% lower in pediatric subjects versus adults with geometric mean ratios of 0.71 (90% CI: 0.50, 1.00) and 0.77 (90% CI: 0.59, 1.02), respectively (Table 8). The observed differences were not considered clinically significant.

Table 8: Multiple-Dose PK Parameters of Emtricitabine and Tenofovir Alafenamide Following Oral Administration with Food in HIV 1 Infected Adults and Pediatric Subjects
Parameter Geometric mean (CV%) Emtricitabine Tenofovir alafenamide
CV = Coefficient of Variation; mcg = microgram; NA = not applicable
*
From intensive PK analysis in trial GS-US-292-0106 in treatment-naïve pediatric subjects with HIV-1 infection
AUClast for tenofovir alafenamide
N=23
§
From intensive PK analysis in trial GS-US-292-0102 in HIV-infected adults treated with emtricitabine+tenofovir alafenamide and elvitegravir+cobicistat
Pediatric Subjects * N=24 N=24
AUC24h (mcg.hr/mL) 14.0 (23.9) 0.16 (55.8)
Cmax (mcg/mL) 2.2 (22.5) 0.14 (64.4)
C24h (mcg/mL) 0.10 (38.9) NA
Adults § N=19 N=19
AUC24h (mcg.hr/mL) 11.6 (16.6) 0.21 (47.3)
Cmax (mcg/mL) 2.0 (20.2) 0.19 (64.6)
C24h (mcg/mL) 0.09 (46.7) NA

Gender and Race

There were no clinically relevant differences in the pharmacokinetics of darunavir, cobicistat, emtricitabine, or tenofovir alafenamide based on gender or race.

Patients with Renal Impairment

Darunavir: The pharmacokinetics of darunavir were not altered in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, estimated by Cockcroft-Gault method, N=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end-stage renal disease taking darunavir co-administered with cobicistat [see Use in Specific Populations (8.6)].

Cobicistat: There were no clinically relevant differences in cobicistat pharmacokinetics observed between subjects with severe renal impairment (creatinine clearance below 30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects [see Use in Specific Populations (8.6)].

Emtricitabine: Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (creatinine clearance less than 30 mL/min, estimated by Cockcroft-Gault method) than in subjects with normal renal function [see Use in Specific Populations (8.6)].

Tenofovir alafenamide: In studies of TAF, no clinically relevant differences in the pharmacokinetics of TAF or its metabolite tenofovir were observed between subjects with severe renal impairment (creatinine clearance of 15–30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Darunavir: There were no clinically relevant differences in the pharmacokinetics of darunavir (600 mg with ritonavir 100 mg twice daily) in subjects with mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8), compared to subjects with normal hepatic function (n=16). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.7)].

Cobicistat: There were no clinically relevant differences in the cobicistat pharmacokinetics between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated [see Use in Specific Populations (8.7)].

Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited [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 patients with mild, moderate (Child-Pugh Class A and B), or severe hepatic impairment (Child-Pugh Class C); [see Use in Specific Populations (8.7)].

Patients with Hepatitis B and/or Hepatitis C Virus Coinfection

Darunavir: In HIV-infected subjects taking darunavir co-administered with ritonavir, the 48-week analysis of the data from clinical trials indicated that hepatitis B and/or hepatitis C virus coinfection status had no apparent effect on the exposure of darunavir.

Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.

Emtricitabine and tenofovir alafenamide: The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.

Pregnancy and Postpartum

The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 9 and Figure 1).

Table 9: Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum
Pharmacokinetics of total darunavir(mean ± SD)2nd Trimester of pregnancyN=73rd Trimester of pregnancyN=6Postpartum (6–12 weeks)N=6
Cmax , ng/mL4340 ± 16164910 ± 9707918 ± 2199
AUC24h , ng.h/mL47293 ± 1905847991 ± 987999613 ± 34862
Cmin , ng/mL168 ± 149184 ± 991538 ± 1344

Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum

Figure 1
(click image for full-size original)

Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e., second or third trimester/postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.

Drug Interactions

Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.

Emtricitabine is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A. It is not an inhibitor or inducer of CYP3A in vivo.

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