Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors
ATC code: J05AF09
Emtricitabine is a synthetic nucleoside analogue of cytidine with activity that is specific to HIV-1, HIV-2 and HBV.
Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which competitively inhibits HIV-1 reverse transcriptase, resulting in DNA chain termination. Emtricitabine is a weak inhibitor of mammalian DNA polymerase α, β and ε and mitochondrial DNA polymerase γ.
Emtricitabine did not exhibit cytotoxicity to peripheral blood mononuclear cells (PBMCs), established lymphocyte and monocyte-macrophage cell lines or bone marrow progenitor cells in vitro. There was no evidence of toxicity to mitochondria in vitro or in vivo.
The 50% inhibitory concentration (IC50) value for emtricitabine against laboratory and clinical isolates of HIV-1 was in the range of 0.0013 to 0.5 µmol/l. In combination studies of emtricitabine with protease inhibitors (PIs), nucleoside, nucleotide and non-nucleoside analogue inhibitors of HIV reverse transcriptase, additive to synergistic effects were observed. Most of these combinations have not been studied in humans.
When tested for activity against laboratory strains of HBV, the IC50 value for emtricitabine was in the range of 0.01 to 0.04 µmol/l.
HIV-1 resistance to emtricitabine develops as the result of changes at codon 184 causing the methionine to be changed to a valine (an isoleucine intermediate has also been observed) of the HIV reverse transcriptase. This HIV-1 mutation was observed in vitro and in HIV-1 infected patients.
Emtricitabine-resistant viruses were cross-resistant to lamivudine, but retained sensitivity to other nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, stavudine, tenofovir, abacavir and didanosine), all non-nucleoside reverse transcriptase inhibitors (NNRTIs) and all PIs. Viruses resistant to zidovudine, didanosine and NNRTIs retained their sensitivity to emtricitabine (IC50 = 0.002 µmol/l to 0.08 µmol/l).
Emtricitabine in combination with other antiretroviral agents, including nucleoside analogues, non-nucleoside analogues and PIs, has been shown to be effective in the treatment of HIV infection in treatment-naïve patients and treatment-experienced patients with stable virological control. There is no experience of the use of emtricitabine in patients who are failing their current regimen or who have failed multiple regimens.
In antiretroviral treatment-naïve adults, emtricitabine was significantly superior to stavudine when both medicinal products were taken in combination with didanosine and efavirenz through 48 weeks of treatment. Phenotypic analysis showed no significant changes in emtricitabine susceptibility unless the M184V/I mutation had developed.
In virologically stable treatment-experienced adults, emtricitabine, in combination with an NRTI (either stavudine or zidovudine) and a protease inhibitor (PI) or an NNRTI was shown to be non-inferior to lamivudine with respect to the proportion of responders (<400 copies/ml) through 48 weeks (77% emtricitabine, 82% lamivudine). Additionally, in a second study, treatment-experienced adults on a stable PI based highly active antiretroviral therapy (HAART) regimen were randomised to a once daily regimen containing emtricitabine or to continue with their PI-HAART regimen. At 48 weeks of treatment the emtricitabine-containing regimen demonstrated an equivalent proportion of patients with HIV RNA <400 copies/ml (94% emtricitabine versus 92%) and a greater proportion of patients with HIV RNA <50 copies/ml (95% emtricitabine versus 87%) compared with the patients continuing with their PI-HAART regimen.
In infants and children older than 4 months, the majority of patients achieved or maintained complete suppression of plasma HIV-1 RNA through 48 weeks (89% achieved ≤400 copies/ml and 77% achieved ≤50 copies/ml).
There is no clinical experience of the use of emtricitabine in infants less than 4 months of age.
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours post-dose. In 20 HIV infected subjects receiving 200 mg emtricitabine daily as hard capsules, steady-state plasma emtricitabine peak concentrations (Cmax), trough concentrations (Cmin) and area under the plasma concentration time curve over a 24-hour dosing interval (AUC) were 1.8 ± 0.7 μg/ml, 0.09 ± 0.07 μg/ml and 10.0 ± 3.1 μg·h/ml, respectively. Steady-state trough plasma concentrations reached levels approximately 4-fold above the in vitro IC90 values for anti-HIV activity.
The absolute bioavailability of emtricitabine from Emtriva 200 mg hard capsules was estimated to be 93% and the absolute bioavailability from Emtriva 10 mg/ml oral solution was estimated to be 75%.
In a pilot study in children and a definitive bioequivalence study in adults, the Emtriva 10 mg/ml oral solution was shown to have approximately 80% of the bioavailability of the Emtriva 200 mg hard capsules. The reason for this difference is unknown. Due to this difference in bioavailability, 240 mg emtricitabine administered as the oral solution should provide similar plasma levels to those observed after administration of one 200 mg emtricitabine hard capsule. Therefore, children who weigh at least 33 kg may take either one 200 mg hard capsule daily or the oral solution up to a maximum dose of 240 mg (24 ml), once daily.
Administration of Emtriva 200 mg hard capsules with a high-fat meal or administration of Emtriva 10 mg/ml oral solution with a low-fat or high-fat meal did not affect systemic exposure (AUC0-∞) of emtricitabine; therefore Emtriva 200 mg hard capsules and Emtriva 10 mg/ml oral solution may be administered with or without food.
In vitro binding of emtricitabine to human plasma proteins was <4% and independent of concentration over the range of 0.02-200 μg/ml. The mean plasma to blood concentration ratio was approximately 1.0 and the mean semen to plasma concentration ratio was approximately 4.0.
The apparent volume of distribution after intravenous administration of emtricitabine was 1.4 ± 0.3 l/kg, indicating that emtricitabine is widely distributed throughout the body to both intracellular and extracellular fluid spaces.
There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose).
Emtricitabine did not inhibit in vitro drug metabolism mediated by the following human CYP450 isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4.
Also, emtricitabine did not inhibit uridine-5'-diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation.
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged 307 ml/min (4.03 ml/min/kg). Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
The pharmacokinetics of emtricitabine are proportional to dose over the dose range of 25-200 mg following single or repeated administration.
Intracellular pharmacokinetics: In a clinical study, the intracellular half-life of emtricitabine-triphosphate in peripheral blood mononuclear cells was 39 hours. Intracellular triphosphate levels increased with dose, but reached a plateau at doses of 200 mg or greater.
Pharmacokinetic parameters were determined following administration of a single dose of 200 mg emtricitabine hard capsules to 30 non-HIV infected subjects with varying degrees of renal insufficiency. Subjects were grouped according to baseline creatinine clearance (>80 ml/min as normal function; 50-80 ml/min as mild impairment; 30-49 ml/min as moderate impairment; <30 ml/min as severe impairment; <15 ml/min as functionally anephric requiring haemodialysis).
The systemic emtricitabine exposure (mean ± standard deviation) increased from 11.8 ± 2.9 μg·h/ml in subjects with normal renal function to 19.9 ± 1.1, 25.0 ± 5.7 and 34.0 ± 2.1 μg·h/ml, in patients with mild, moderate and severe renal impairment, respectively.
In patients with ESRD on haemodialysis, approximately 30% of the emtricitabine dose was recovered in dialysate over a 3-hour dialysis period which had been started within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and dialysate flow rate of approximately 600 mL/min).
The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects with varying degrees of hepatic insufficiency. In general, emtricitabine pharmacokinetics in HBV infected subjects were similar to those in healthy subjects and in HIV infected subjects.
Pharmacokinetic data are not available in the elderly (over 65 years of age).
Although the mean Cmax and Cmin were approximately 20% higher and mean AUC was 16% higher in females compared to males, this difference was not considered clinically significant.
No clinically important pharmacokinetic difference due to ethnicity has been identified.
In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months up to 18 years) are similar to those seen in adults.
The mean AUC in 77 infants, children and adolescents receiving 6 mg/kg emtricitabine once daily as oral solution or 200 mg emtricitabine as hard capsules once daily was similar to the mean AUC of 10.0 μg·h/ml in 20 adults receiving 200 mg hard capsules once daily.
In an open-label, non-comparative study, pharmacokinetic data were obtained from 20 neonates of HIV infected mothers who received two 4-day courses of emtricitabine oral solution between the first week of life and 3 months of age at a dose level of 3 mg/kg once daily. This dose is half of that approved for infants aged 4 months and over (6 mg/kg). The apparent total body clearance at steady-state (CL/F) increased with age over the 3-month period with a corresponding decrease in AUC. Plasma emtricitabine exposure (AUC) in infants up to 3 months of age who received 3 mg/kg emtricitabine once daily was similar to that observed using 6 mg/kg daily doses in HIV infected adults and children aged 4 months and over.
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
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