Indications
Tenofovir alafenamide is primarily indicated for the treatment of hepatitis B virus infection in adults and pediatric patients aged 12 years and older who have compensated liver disease. Additionally, in combination with emtricitabine and other antiretroviral agents, it serves as a therapeutic option for HIV-1 infection in both adolescent and adult patients weighing over 35 kg. This combination is also utilized for the prevention of HIV-1 infection in high-risk adolescent and adult populations, excluding those at risk from receptive vaginal sex. Furthermore, when combined with specific antiretrovirals that do not include protease inhibitors requiring a CYP3A inhibitor, it can be employed in pediatric patients weighing between 25-35 kg. The combination product with emtricitabine and bictegravir is recognized as a complete regimen for HIV-1 infection in treatment-naive patients or those who have been virologically suppressed for at least three months without a history of treatment failure. It can also replace an existing regimen in virologically-suppressed patients (HIV-1 RNA less than 50 copies per mL) without known resistance to bictegravir or tenofovir. Additional combination products including tenofovir alafenamide, such as those with elvitegravir, cobicistat, emtricitabine, and those with emtricitabine, rilpivirine, are applicable for treating HIV-1 in patients older than 12 years, either treatment-naive or virologically suppressed for at least 6 months. Moreover, a combination regimen including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for HIV-1 management in adults both without prior treatment or virologically suppressed for 6 months, without resistance to darunavir or tenofovir.
Pharmacodynamics
Tenofovir alafenamide acts as a potent inhibitor of hepatitis B virus replication. Compared to tenofovir disoproxil, tenofovir alafenamide offers improved renal tolerance, attributable to lower plasma concentrations. In clinical settings, tenofovir alafenamide has demonstrated a five-fold increase in antiviral activity against HIV-1 relative to tenofovir disoproxil.
Absorption
Tenofovir alafenamide is structurally modified with a lipophilic group that masks its negative charge, thereby enhancing its oral bioavailability compared to the parent compound, tenofovir. It exhibits high stability in plasma, and post-administration, maintains low plasma concentrations. Upon oral administration, the prodrug is quickly absorbed in the gastrointestinal tract, achieving a peak plasma concentration of approximately 16 ng/ml within 2 hours, correlating to about 73% of the administered dose, with an area under the curve (AUC) of 270 ngh/mL. The compound enters hepatocytes via passive diffusion through organic anion transporters 1B1 and 1B3. Additionally, when administered with a high-fat meal, there is a 65% increase in its systemic exposure.
Metabolism
Tenofovir alafenamide requires hydrolysis by cathepsin A or carboxylesterase 1 to convert into its active form, tenofovir. Given its significant plasma stability, activation predominantly occurs within target cells. Once activated, tenofovir undergoes further metabolism and is predominantly detected as uric acid in plasma within 1-2 days post-activation.
Mechanism of Action
Tenofovir Alafenamide is characterized by a significantly reduced plasma concentration, approximately 91% lower, compared to tenofovir disoproxil. Notably, it achieves an intracellular presence about 20 times higher, primarily due to its extended systemic exposure and enhanced intracellular accumulation of the active metabolite, tenofovir diphosphate. This compound preferentially accumulates in peripheral blood mononuclear cells rather than in red blood cells. Upon activation, tenofovir exerts its effects through multiple mechanisms, including the inhibition of viral polymerase, leading to chain termination and subsequent inhibition of viral synthesis.
