Source: Health Products Regulatory Authority (ZA) Revision Year: 2015 Publisher: Macleods Pharmaceuticals SA (Pty) Ltd, Stand 6 D & E, Growthpoint Business Park, Halfway House, Midrand, South Africa
Pharmacological classification: A 20.2.8 Antimicrobial (Chemotherapeutic) Agents, Antiviral agents
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI). Emtricitabine, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.
Tenofovir disoproxil fumarate is a nucleoside reverse transcriptase inhibitor (NRTI). Tenofovir disoproxil fumarate, also known as tenofovir DF, is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNApolymerases α, β, and mitochondrial DNApolymerase γ.
In combination studies evaluating the in vitro antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysisofthese isolates identifiedthe M184I/V and/or K65R amino acidsubstitutions inthe viral RT.
Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognised. The M184V/I and/or K65R substitutions selected in vitro by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these medicines may occur inpatientswhose virus harbourseitherorbothofthese amino acidsubstitutions.
The pharmacokinetic properties of emtricitabine are summarised in Table 1.
Following oral administration of emtricitabine (200 mg), emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1-2 hours post-dose.
In vitro binding of emtricitabine to human plasma proteins is <4% and is independent of concentration over the range of 0,02-200 µg/mL.
Following administration ofradiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a singleoraldoseofemtricitabine (200mg), the plasmaemtricitabine half-life isapproximately 10 hours.
The pharmacokinetic properties of tenofovir disoproxil fumarate are summarised in Table 1.
Following oral administration of tenofovir, maximum tenofovir serum concentrations are achieved in 1,0 ± 0,4 hour.
In vitro binding of tenofovir to human plasma proteins <0,7% and is independent of concentration over the range of 0,01-25 µg/mL.
Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours.
Table 1. Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in 1 Adults:
| Emtricitabine | Tenofovir | |
|---|---|---|
| Fasted Oral Bioavailability2 (%) | 92 (83,1-106,4) | 25 (NC-45,0) |
| Plasma Terminal Elimination Half-Life2 (hr) | 10 (7,4-18,0) | 17 (12,0-25,7) |
| Cmax3 ( g/mL) | 1,8 ± 0,724 | 0,30 ± 0,09 |
| AUC3 ( g•hr/mL) | 10,0 ± 3,124 | 2,29 ± 0,69 |
| CL/F3 (mL/min) | 302 ± 94 | 1043 ± 115 |
| CLrenal3 (mL/min) | 213 ± 89 | 243 ± 33 |
1 NC = Not calculated
2 Median (range)
3 Mean (± SD)
4 Data presented as steady state values
EMTROCTABLETSmay beadministeredwithorwithout food. AdministrationofEMTROCTABLETS following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delays the time of tenofovir Cmax by approximately 0,75 hour. The mean increases in tenofovir AUC and Cmax are approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. Emtricitabine systemic exposures (AUC and Cmax) are unaffected when EMTROC TABLETSis administered with either a high fat or a light meal.
Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in children (<18 years) or in elderly (>65 years) (see WARNINGS AND SPECIAL PRECAUTIONS, Paediatric use, Geriatric use).
The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment (See WARNINGS AND SPECIALPRECAUTIONS, Renal impairment). In patients with creatinine clearance <50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for EMTROC TABLETS be modified in patients with creatinine clearance 30-49 mL/min. EMTROC TABLETS should not be used in patients with creatinine clearance <30 mL/min and in patients with end-stage renal disease requiring dialysis (see WARNINGS AND SPECIALPRECAUTIONS, Renal impairment).
The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil fumarate have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of EMTROC TABLETS or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.
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