Elvitegravir cobicistat emtricitabine tenofovir clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]
Clinical Pharmacology
Pharmacodynamics
Effects on Electrocardiogram
Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known.
The effect of multiple doses of elvitegravir 125 and 250 mg (0.83 and 1.67 times the dose in STRIBILD) (coadministered with 100 mg RTV to boost the blood levels of elvitegravir) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 msec. In this study, there was no clinically relevant prolongation of the QTc interval.
The effect of a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 msec, the threshold for regulatory concern. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400 mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation.
Pharmacokinetics
- Absorption and Bioavailability
STRIBILD: Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the conversion of tenofovir DF (see Table 7 for additional pharmacokinetic parameters).
- Effect of Food on Oral Absorption
Relative to fasting conditions, the administration of single dose STRIBILD with a light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.
Relative to fasting conditions, the administration of single dose STRIBILD with a high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.
STRIBILD should be taken with food.
- Distribution
Elvitegravir: Elvitegravir is 98–99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73.
Cobicistat: Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02–200 micrograms per mL.
Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 micrograms per mL.
- Metabolism
Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.
Cobicistat: Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
Emtricitabine and tenofovir are not significantly metabolized.
- Elimination
Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.
Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.
Emtricitabine and tenofovir are primarily excreted in the urine by a combination of glomerular filtration and active tubular secretion.
Special Populations
- Patients with Renal Impairment
Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis.
- Patients with Hepatic Impairment
Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied.
Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.
- Hepatitis B and/or Hepatitis C Virus Co-infection
Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.
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: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
- Race
Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.
Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.
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 VIREAD.
- Gender
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.
- Pediatric Patients
Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established.
- Geriatric Patients
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations].[1]
References
Adapted from the FDA Package Insert.