Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530 Customer Care: 080 222 6662
Pharmacological class: A 20.2.8 Antimicrobial (chemotherapeutic) agents - Antiviral agents
ATC code: J05AR17
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of 2'-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits HIV replication through incorporation into viral deoxyribonucleic acid (DNA) by the HIV reverse transcriptase (RT), which results in DNA chain-termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ.
Tenofovir alafenamide is a phosphonamidite prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Plasma exposure to tenofovir alafenamide allows for permeation into cells and then tenofovir alafenamide is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is intracellularly phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV RT, which results in DNA chain termination.
Tenofovir has activity against HIV-1, HIV-2 and HBV. In vitro studies have shown that both tenofovir and emtricitabine can be fully phosphorylated when combined into cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184I/V and/or K65R amino acid substitutions in the viral RT.
In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in reduced susceptibility to tenofovir.
In a clinical study of treatment-naïve patients (emtricitabine + tenofovir + efavirenz vs zidovudine + lamivudine + efavirenz), resistance analysis was performed on HIV isolates from all virologic failures with greater than 400 copies/mL of HIV-1 RNA at week 144 or early discontinuation. Development of efavirenz resistance-associated mutations occurred most frequently and was similar between the treatment groups.
The M184V amino acid mutation, associated with resistance to emtricitabine and lamivudine, was observed in 2/19 analysed subject isolates in the emtricitabine/tenofovir group and in 10/29 analysed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of this study, no subjects have developed a detectable K65R or K70E substitution in their HIV-1 as analysed through standard genotypic analysis.
The M184V amino acid substitution, associated with resistance to emtricitabine and lamivudine, was observed in 2/12 (17 %) analyses patient isolates in the emtricitabine/tenofovir group and in 7/22 (32 %) analysed patient isolates in the zidovudine/lamivudine group.
Emtricitabine resistant isolates were selected in vivo and in vitro. Genotypic analysis of these isolated showed that reduced susceptibility to emtricitabine was associated with a RT mutation at codon 184 which resulted in an amino acid substitution from methionine to valine or isoleucine (M184V/I).
Emtricitabine resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretrovirals. Viral isolates from treatment-naïve patients with virologic failure showed > 20-fold reduced susceptibility to emtricitabine. These isolates were showed that the resistance was due to M184V/I mutation in the HIV RT gene.
The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir or didanosine.
HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbours the K65R or K70E mutations.
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R mutation in RT and showed a 2 to 4-fold reduction in susceptibility to tenofovir.
Tenofovir-resistant isolated of HIV-1 have also been recovered from some patients treated with tenofovir in combination with certain antiretrovirals. In treatment-naïve patients, 8/47 (17 %) isolates from patients on tenofovir + lamivudine + efavirenz through week 144 showed greater than 1,4-fold (median 3,7) reduced susceptibility in cell culture to tenofovir. Isolates from treatment-experienced patients failing tenofovir through week 96 showed greater 1,4-fold (median 2,7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1 RT gene resulting in the K65R amino acid substitution.
Cross-resistance among certain NRTIs has been recognised. The M184V/I and/or K65R mutations selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from patients failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these medicines may occur in patients whose virus harbours either or both amino acid substitutions.
Emtricitabine-resistant isolates (M184V/I) were resistant to lamivudine and zalcitabine but retained susceptibility to didanosine, stavudine, tenofovir, zidovudine and NNRTIs (delavirdine, efavirenz and nevirapine), in vitro. Isolates from heavily treatment-experienced patients containing the M184V/I amino acid substitution in the context of other NRTI resistance associated substitution may retain susceptibility to tenofovir. HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir and zalcitabine, demonstrated reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.
HIV-1 isolates from patients whose HIV-1 expressed a mean of 3'-zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N) showed a 3,1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT showed reduced susceptibility to tenofovir
In combination studies evaluating the in-cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed.
Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1 to 2 hours post-dose. According to studies performed, emtricitabine systemic exposure was unaffected when administered with food. Following administration of food in healthy subjects, peak plasma concentrations were observed approximately 1-hour post-dose for tenofovir alafenamide. Relative to fasting conditions, the administration of tenofovir alafenamide with a high fat meat resulted in a decrease in tenofovir alafenamide Cmax and an increase in AUC.
According to studies, the in vitro binding of emtricitabine to human plasma proteins was ˂4% and independent of concentration over the range of 0,02–200 ug/mL. At peak plasma concentration, the mean plasma to blood drug concentration ratio was approximately 1,0 and the mean semen to plasma drug concentration was approximately 4,0.
According to studies, the in vitro binding of tenofovir to human plasma proteins is ˂0,7% and is independent of concentration over the range of 0,01–25 ug/mL. Ex vivo binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies performed was approximately 80%.
Data from in vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. Following administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the dose was recovered in the urine as three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). No other metabolites were identifiable.
Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for >80% of an oral dose. Data from in vitro studies show that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and macrophages; and by caboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite tenofovir diphosphate.
In vitro, tenofovir is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administration with the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not significantly affected.
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 emtricitabine is recovered in urine as three metabolites. According to studies, the systemic clearance of emtricitabine averaged 307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Renal excretion of intact tenofovir alafenamide is a minor pathway with ˂1% of the dose eliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0,51 and 32,37 hours, respectively. Tenofovir is renally eliminated by both glomerular filtration and active tubular secretion.
No clinically relevant pharmacokinetic differences due to age, gender or ethnicity have been identified for emtricitabine, or tenofovir alafenamide.
No clinically relevant differences in tenofovir alafenamide, or tenofovir alafenamide pharmacokinetics were observed between healthy subjects and patients with severe renal impairment (estimated CrCl ≥15 mL/min and ˂30 mL/min).
No clinically relevant differences in tenofovir alafenamide pharmacokinetics were observed in patients with end stage renal disease on chronic haemodialysis as compared to those with normal renal function.
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.
The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in patients co-infected with HBV and/or HCV.
TAFBIN pharmacokinetics have not been evaluated in the elderly.
TAFBIN pharmacokinetics have not been evaluated in children.
Non-clinical date on emtricitabine reveal no genotoxicity, carcinogenic potential, or toxicity to reproduction and development relevant to humans.
Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidneys as the primary target organs of toxicity. Bone toxicity was observed as reduced BMD. A minimal infiltration of histocytes was observed in the eye of dogs at high exposure to tenofovir alafenamide.
Tenofovir alafenamide was not mutagenic or clastogenic.
Because there is a lower tenofovir exposure in rats and mice after the administration of tenofovir alafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies and a rat peri-postnatal study were conducted only with tenofovir disoproxil fumarate which revealed no relevant carcinogenic potential and toxicity to reproduction and development. Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, the viability index and weight of pups were reduced in a peri-postnatal toxicity study at maternally toxic doses.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.