In this article, we will discuss about Tenofovir (Overview). So, let’s get started.
Mechanism of action
Tenofovir is chemically identified as 9-R-2-phosphonomethoxypropyl adenine (PMPA), and is a potent antiviral inhibitor belonging to the acyclic nucleoside phosphonate family. It is an ester prodrug for the antiretroviral, tenofovir, and is poorly bioavailable as a result of two negative charges formed by phosphonyl groups. After oral administration, TDF is first hydrolyzed by carboxylesterase in the intestinal walls and subsequently hydrolyzed by phosphodiesterase during its first passage through the liver to form tenofovir. Tenofovir enters cells through organic anion transporters 1 and 3. Once inside the cell, tenofovir is phosphorylated by adenylate kinase to form tenofovir monophosphate (TFV-MP). A second conversion occurs by nucleotide diphosphate kinase to form tenofovir
diphosphate (TFV-DP) from TFV-MP TFV-DP is the active antiviral agent that competes with the naturally occurring nucleotide counterpart deoxyadenosine 5′-triphosphate to inhibit viral reverse transcriptase. Inhibition of the natural substrate by incorporation of TFV-DP into the viral DNA chain terminates DNA elongation and stops further DNA synthesis. TFV-DP is also a weak inhibitor of cellular DNA polymerases alpha, beta, and gamma. As a result, incorporation of TFV-DP into the viral DNA chain has to occur prior to the polymerization of the viral DNA to be effective. Excess TFV-DP that is unable to incorporate into viral DNA can be retained in the cell and dephosporylated by endogenous phosphatases. Once dephosphorylated, tenofovir can undergo phosphorylation again forming TFV-MP and TFV-DP or can exit the cell as tenofovir by the transporters multidrug resistance protein (MDRP) 1, 4, & 5 or breast cancer resistance protein. After exiting the cell, tenofovir is subject to systemic elimination.
In vitro, tenofovir exhibits synergistic and additive activity when combined with certain antiretrovirals and demonstrates no antagonistic interactions in their presence. Strong synergism has been seen with ZDV, and nevirapine (NVP), while mild synergism has been noted in combination with didanosine (ddI), and nelfinavir (NFV). Additive inhibition has been reported when co-administered with abacavir (ABC), lamivudine (3TC), stavudine (d4T), indinavir (IDV), ritonavir (RTV), and saquinavir (SQV). Tenofovir demonstrates minimal cytotoxicity while showing immunomodulatory effects. Data from both human and murine cell lines in HIV-1 infected T-lymphocytes and peripheral blood mononuclear cells (PBMC) show tenofovir concentrations required to kill 50% of cells occurs at 22 μmol/L and 29 μmol/L, respectively. Cytotoxicity of human renal proximal
tubule epithelial cells and epithelium to maintain tight junctions are displayed at higher tenofovir concentrations (up to 2 mmol/L) and do not inhibit the integrity or growth of these cells.
Immunomodulatory effects of tenofovir are demonstrated through stimulation of cytokines, which can interfere with HIV replication and chemokines, which block HIV entry into cells.
Recommended Dose in Adults
For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg Tenofovir disoproxil fumarate (VIREAD) tablet once daily taken orally, without regard to food.
For adults unable to swallow Tenofovir disoproxil fumarate (VIREAD) tablets, the oral powder formulation (7.5 scoops) may be used.
In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.
Recommended Dose in Pediatric Patients (2 to Less Than 18 Years of Age)
For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of Tenofovir disoproxil fumarate (VIREAD) is 8 mg of tenofovir disoproxil fumarate per
kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets. Tenofovir disoproxil fumarate (VIREAD) oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate (VIREAD) oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer Tenofovir disoproxil fumarate (VIREAD) oral powder in a liquid as the powder may float on top of the liquid even after stirring.
Tenofovir disoproxil fumarate (VIREAD) is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
Dosing Recommendations for Pediatric Patients >2 Years of Age Using VIREAD Oral Powder
Body Weight – Oral Powder Once Daily
Kilogram (kg) Scoops of Powder
10 to <12 – 2
12 to <14 – 2.5
14 to <17 – 3
17 to <19 – 3.5
19 to <22 – 4
22 to <24 – 4.5
24 to <27 – 5
27 to <29 – 5.5
29 to <32 – 6
32 to <34 – 6.5
34 to <35 – 7
≥35 – 7.5
Dosing Recommendations for Pediatric Patients ≥2 Years of Age and Weighing ≥17 kg Using VIREAD Tablets
Body Weight Kilogram (kg) – Tablets Once Daily
17 to <22 – 150 mg
22 to <28 – 200 mg
28 to <35 – 250 mg
≥35 – 300 mg
Warnings and Precautions
• New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with VIREAD. Monitor CTCI and serum phosphorus in patients at risk. Avoid administering VIREAD with concurrent or recent use of nephrotoxic drugs.
• Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA, COMPLERA, and
TRUVADA). Do not administer in combination with HEPSERA
• HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection.
• Decreases in bone mineral density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis
or bone loss.
• Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy.
• Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment.
• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification.