Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Emtricitabine (Emtriva)1

      •  

        Structural Comparison between Cytosine (top), Lamivudine (Middle) and Emtricitabine (Bottom)⁶

    • As shown above, emtricitabine (Emtriva) is very closely chemically related to lamivudine (Epivir).¹ 

      • These drugs exhibit similar pharmacodynamic characteristics.

      • At least in vitro, emtricitabine appears about 10 times more active compared to lamivudine.

      • Emtricitabine following cell entry (passive diffusion) is initally phosphorylated by deoxycytidine kinase and ultimately other cellular kinases to the active drug form, emtricitabine 5'-triphosphate.

        • Accordingly, emtricitabine can be described as a "prodrug", requiring triphosphorylation to the active form.

      • Low toxicity associated with both emtricitabine and lamivudine is due to these agents limited tendency to bind  to human DNA polymerases (low affinity for human DNA polymerase).¹

    • Mutations and Resistance to Emtricitabine:

      • Resistance to the action of emtricitabine as a result of mutations in viral polymerase occurs by mechanism identical to that observed and described earlier for lamivudine.¹¹   

        • If emtricitabine is used as monotherapy, this resistance can develop within a few weeks, due to the single point mutation at position 184 of reverse transcriptase.¹¹ 

        • This mutation is the methionine to valine change occurring at codon 184 (amino acid 184); furthermore, the mutation may occur less often with emtricitabine compared to lamivudine.¹ 

          • More recent studies have also noted that virological failure is more likely with lamivudine compared to emtricitabine when combined with other antiretroviral drugs.¹²  

            • Generally, lamivudine (Epivir) and emtricitabine (Emtriva) are viewed as interchangeable in "first-line" tenofovir/efavirenz and tenofovir/nevirapine combination antriretroviral therapy (cART; HAART).¹²  

            • In order to evaluate this conclusion, a clinical trial on cART-naïve patients with HIV-1 infection was performed.

              • Outcome measures included:

                • Week 48 virological failure

                • Treatment analysis

                • Time to HIV-RNA <400 copies/cc within 48 weeks and

                • Virologic failure within 240 weeks after at least one HIV-RNA <400 copies/cc result.

            • Study conclusions indicated that emtricitabine in combination anti-retroviral treatment appeared associated with improved virological response compared to lamivudine.¹²  

              • This trial utilized the Dutch nationwide HIV Cohort.

          • Another similar study considering emtricitabine and lamivudine resistance profiles and tenofovir-containing protocols involved comparing the selection frequency of the codon 184 mutation in HIV-infected patients.¹³  

            • These patients had experienced virologic failure while receiving emtricitabine or lamivudine administered with tenofovir and either efavirenz or ritonavir-boosted protease inhibitor such as lopinavir or atazanavir.¹³  

              • Patient information from two French clinical centers was evaluated retrospectively.

              • Patients included in the study had experienced virologic suppression, described as plasma HIV RNA < 200 copies/cc for a period of time of six months or longer prior to first virologic failure.

                • Virological failure was defined as at least two determinations of plasma HIV RNA  ≥ 200 copies/cc.

            • The results suggested that emtricitabine and lamivudine exhibited differing resistance profiles if administered in combination with tenofovir and either efavirenz or a ritonavir-boosted protease inhibitor drug.

              • The prevalence of the mutation at codon 184, the important resistance mutation, was lower in patients receiving emtricitabine and tenofovir compared to patients receiving lamivudine and tenofovir.¹³  

        • Emtricitabine also exhibits a low level of resistance development when given in combination with efavirenz and didanosine.⁴

      • Pharmacokinetics:

        • Oral bioavailability of emtricitabine exceeds 90% with rapid absorption.¹  

          • This agent may be taken without regard to meals, although food may reduce the C_max, the area under the curve (AUC) is unaffected.

            • When compared to other nucleoside analog-type agents, emtricitabine exhibits a relatively slow systemic clearance with an elimination half-life (t_½) of about 9 hours.^1,11

            • "Mean (±95% CI) Steady_State Plasma Emtricitabine

              Concentrations in HIV-Infected Adults (N=20)"

              Attribution:  Figure above corresponds to Figure 1 in NDA 21-896. http://www.drugbank.ca/system/fda_labels/DB00879.pdf?1265922807

    • Furthermore the estimated half-life of the active drug, emtricitabine-5'-triphosphate is even longer, up to 39 hours.

    • This extended half-life provides a pharmacokinetic reason supporting a single daily dosing.

    • With respect to excretion, emtricitabine is eliminated unchanged in the urine following glomerular filtration as well as active tubular secretion.

    • Dose reduction may be appropriate in individuals with creatinine clearance of < 50 mL/min.¹ 

    • Emtricitabine is also available as an oral solution which contains propylene glycol.⁷  

      • This formulation is contraindicated in pregnant women, young children, patients with hepatic or renal failure and in those individuals also taking metronidazole or disulfiram.⁷

    • Adverse Effects: 

      • Emtricitabine (Emtriva), similar to the other nucleoside analogues, exhibits toxicity potential as secondary to interaction with human mitochondrial DNA enzymes, for example mitochondrial DNA polymerases γ.¹¹  

        • Such interactions may result in myopathies and neuropathies and may cause of hepatic steatosis potentially leading to primary lactic acidosis syndrome.

        • In vitro studies demonstrated that emtricitabine 5'-triphosphate, the active intracellular form, did not appreciably influence either cellular or mitochondrial DNA polymerase enzymic function.

          • Comparing emtricitabine 5' triphosphate with the very similar agent lamivudine 5' triphosphate, Emtriva was about 20 times less active with respect to mitochondrial DNA polymerase (pol γ) inhibition.¹¹

        • Emtricitabine is considered one of the least toxic antiviral agents, much like lamivudine,  with relatively few substantially adverse reactions.¹  

          • However, emtricitabine may predispose to skin hyperpigmentation particularly in "sun-exposed" areas.

            • Skin hyperpigmentation was considered "very common:" (≥ 10%) in pediatric patients.¹⁵

          • Furthermore, since emtricitabine exhibits in vitro activity against hepatitis B virus (HBV) caution is appropriate when using this agent in those patients infected both with HIV and HBV and also more generally in regions with high HBV prevalence.

            • The concern is that with abrupt emtricitabine discontinuation, by analogy to observations with lamivudine, may lead to HBV replication rebound with worsening hepatitis.¹ 

        • Overall the most common adverse effects following emtricitabine administration include insomnia, nausea, headache, and rash.⁷ 

          • Some occurrence of hyperpigmentation (palms or soles) has also been reported at an overall frequency of about 3% although more frequently noted in African Americans (up to 13%).⁷ 

          • Hyperpigmentation in HIV-Infected Patients Receiving Emtriva¹⁴

    • Therapeutics:

      • Emtricitabine (Emtriva) is used in combination with tenofovir, either alone in the two drug protocol or in combination with efavirenz, rilpivirine, or elvitegravir plus cobicistat which is a boosting agent.⁷ 

      • Tenofovir and emtricitabine in combination has been suggested as:⁷ 

        • Pre-exposure prophylaxis with the intent of reducing HIV infection in men who have sex with men

        • In heterosexually active individuals and

        • In those who inject drugs.⁷   

      • Emtricitabine is a recommended agent, as part of a multidrug protocol, for initial treatment of HIV in antiretroviral drug-naïve patients.¹⁶ 

        • At this time (2015), there are five recommended regimens for antiretroviral therapy in antiretroviral drug-naïve individuals.¹⁶

          • For the regimens involve "integrase strand transfer inhibitor"-based protocols and one ritonavir-boosted protease inhibitor-based protocol.

            • Integrase strand transfer inhibitor-based regimens include:

              • (1) Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC for those patients who are HLA-B *5701 negative.

              • (2) Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine.

              • (3) Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine [restricted for patients with creatinine clearance >70 mL/min prior to antiretroviral therapy].

              • (4) Raltegravir with tenofovir disoproxil fumarate/emtricitabine.

            • The single ritonovir-boosted protease inhibitor protocol involves combination of darunavir/ritonavir with tenofovir disoproxil fumarate/emtricitabine.¹⁶

      •  

        Emtricitabine (Emtriva) Formulation Examples