Emtricitabine clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]
Clinical Pharmacology
Mechanism of Action
Emtricitabine is an antiviral drug.
Pharmacokinetics
Adults
The pharmacokinetics of emtricitabine were evaluated in healthy subjects and HIV-1-infected subjects. Emtricitabine pharmacokinetics are similar between these populations.
Figure 1 shows the mean steady-state plasma emtricitabine concentration-time profile in 20 HIV-1-infected subjects receiving EMTRIVA capsules.
Figure 1 Mean (± 95% CI) Steady-State Plasma Emtricitabine Concentrations in HIV-1-Infected Adults (N=20)
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Absorption
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of EMTRIVA capsules to 20 HIV-1-infected subjects, the (mean ± SD) steady-state plasma emtricitabine peak concentration (Cmax) was 1.8 ± 0.7 µg/mL and the area-under the plasma concentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 µg∙hr/mL. The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 µg/mL. The mean absolute bioavailability of EMTRIVA capsules was 93% while the mean absolute bioavailability of EMTRIVA oral solution was 75%. The relative bioavailability of EMTRIVA oral solution was approximately 80% of EMTRIVA capsules.
The multiple dose pharmacokinetics of emtricitabine are dose proportional over a dose range of 25–200 mg.
Distribution
In vitro binding of emtricitabine to human plasma proteins was less than 4% and independent of concentration over the range of 0.02–200 µg/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.
Metabolism
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP450 enzymes. Following administration of 14C-emtricitabine, complete recovery of the dose was achieved in urine (~86%) and feces (~14%). Thirteen percent (13%) of the dose was recovered in urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (~4% of dose). No other metabolites were identifiable.
Elimination
The plasma emtricitabine half-life is approximately 10 hours. The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption
EMTRIVA capsules and oral solution may be taken with or without food. Emtricitabine systemic exposure (AUC) was unaffected while Cmax decreased by 29% when EMTRIVA capsules were administered with food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC) and Cmax were unaffected when 200 mg EMTRIVA oral solution was administered with either a high-fat or low-fat meal.
Special Populations
Race and Gender
The pharmacokinetics of emtricitabine were similar in adult male and female subjects and no pharmacokinetic differences due to race have been identified.
Pediatric Patients
The pharmacokinetics of emtricitabine at steady state were determined in 77 HIV-1-infected pediatric subjects, and the pharmacokinetic profile was characterized in four age groups (Table 6). The emtricitabine exposure achieved in pediatric subjects receiving a daily dose of 6 mg/kg up to a maximum of 240 mg oral solution or a 200 mg capsule is similar to exposures achieved in adult subjects receiving a once-daily dose of 200 mg.
The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg once daily × 4 days) during the first 3 months of life. The AUC observed in neonates who received a daily dose of 3 mg/kg of emtricitabine was similar to the AUC observed in pediatric subjects ages 3 months to 17 years who received a daily dose of emtricitabine as a 6 mg/kg oral solution up to 240 mg or as a 200 mg capsule (Table 6).
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Geriatric Patients
The pharmacokinetics of emtricitabine have not been fully evaluated in the elderly.
Patients with Impaired Renal Function
The pharmacokinetics of emtricitabine are altered in subjects with renal impairment [See Warnings and Precautions (5.4)]. In adult subjects with creatinine clearance less than 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmaxand AUC of emtricitabine were increased due to a reduction in renal clearance (Table 7). It is recommended that the dosing interval for EMTRIVA be modified in adult patients with creatinine clearance less than 50 mL/min or in adult patients with ESRD who require dialysis [See Dosage and Administration (2.5)]. The effects of renal impairment on emtricitabine pharmacokinetics in pediatric patients are not known.
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Hemodialysis
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Patients with Hepatic Impairment
The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment, however, emtricitabine is not metabolized by liver enzymes, so the impact of liver impairment should be limited.
Assessment of Drug Interactions
At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5'-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP mediated interactions involving emtricitabine with other medicinal products is low.
EMTRIVA has been evaluated in healthy volunteers in combination with tenofovir disoproxil fumarate (DF), zidovudine, indinavir, famciclovir, and stavudine. Tables 8 and 9 summarize the pharmacokinetic effects of coadministered drug on emtricitabine pharmacokinetics and effects of emtricitabine on the pharmacokinetics of coadministered drug.[1]
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References
Adapted from the FDA Package Insert.