VEMLIDY is a novel, targeted prodrug of tenofovir

VEMLIDY delivers tenofovir to hepatocytes more efficiently than tenofovir disoproxil fumarate (TDF)1-4

VEMLIDY® (tenofovir alafenamide) mechanism of action (MOA) image. See Full Prescribing Info, including BOXED WARNING

THOMAS SEPE, MD

Director of the Liver Center University Gastroenterology, Providence, RI

See an overview of the VEMLIDY MOA
and its pharmacokinetics.

Review the VEMLIDY mechanism of action (MOA) and its pharmacokinetics in this presentation by Thomas Sepe, MD. Dr. Sepe is the Director of the Liver Center at University Gastroenterology in Providence, RI.

Watch a video on the pivotal clinical trial results.
  1. Agarwal K, Fung SK, Nguyen TT, et al. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J Hepatol. 2015;62:533-540.
  2. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196-206.
  3. Chan HLY, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185-195.
  4. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet. 2004;43:595-612.
  5. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49:1898-1906.
  6. Lou L. Advances in nucleotide antiviral development from scientific discovery to clinical applications: tenofovir disoproxil fumarate for hepatitis B. J Clin Transl Hepatol. 2013;1:33-38.
  7. Murakami E, Wang T, Park Y, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother. 2015;59:3563-3569.
  8. Ray AS, Fordyce MW, Hitchcock MJ. Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus. Antiviral Res. 2016;125:63-70.
  9. VEMLIDY Prescribing Information, Foster City, CA: Gilead Sciences, Inc.; February 2019.
*Plasma half-life: VEMLIDY=30.6 minutes (0.51 hour)1; TDF=0.41 minutes.5

89%

Lower concentrations of tenofovir in the plasma with VEMLIDY vs TDF, resulting in reduced systemic exposure2,5

WHY A PRODRUG?

  • Tenofovir does not readily cross cell membranes and is poorly absorbed after oral administration due to 2 negative charges on the molecule6,7
  • Prodrugs of tenofovir are required for better absorption6
  • Both VEMLIDY and TDF are prodrugs of tenofovir and have demonstrated increased cellular permeability and oral bioavailability compared with tenofovir6,7

VEMLIDY PROVIDES GREATER PLASMA STABILITY THAN TDF

  • VEMLIDY is a novel, targeted phosphonamidate prodrug of tenofovir1
  • TDF is an ester prodrug5
  • The phosphonamidate group provides greater plasma stability in VEMLIDY than TDF1-4

HOW DOES VEMLIDY COMPARE TO TDF?

  • VEMLIDY breaks down less readily in the plasma than TDF for more efficient drug delivery into the hepatocytes1-4
  • 89% less tenofovir in the plasma than TDF allows for VEMLIDY to be given at approximately 1/10th the dose of TDF1,2,5,8

Warnings and Precautions

  • Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients: Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and, if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: POST TREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B

  • Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Warnings and Precautions

  • Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients: Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and, if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used.
  • New Onset or Worsening Renal Impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of VEMLIDY, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration.
  • Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including tenofovir DF. Discontinue VEMLIDY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

Adverse Reactions

Most common adverse reactions (incidence ≥5%; all grades) were headache, abdominal pain, cough, back pain, fatigue, nausea, arthralgia, diarrhea, and dyspepsia.

Drug Interactions

  • Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions.
  • Coadministration of VEMLIDY is not recommended with the following: oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John’s wort. Such coadministration is expected to decrease the concentration of tenofovir alafenamide, reducing the therapeutic effect of VEMLIDY. Drugs that strongly affect P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) activity may lead to changes in VEMLIDY absorption.

Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

  • Testing Prior to Initiation: HIV infection.
  • Prior to or when initiating, and during treatment: On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
  • Dosage in Adults: 1 tablet taken once daily with food.
  • Renal Impairment: Not recommended in patients with end stage renal disease (ESRD; eCrCl <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment.
  • Hepatic Impairment: Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

INDICATION

VEMLIDY is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease.

Please click here to see full Prescribing Information for VEMLIDY, including BOXED WARNING.