title: Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults.
abstract: BACKGROUND
  Tenofovir alafenamide (formerly GS-7340) is a new oral prodrug of tenofovir, a nucleotide analogue that inhibits HIV-1 reverse transcription. Unlike the currently marketed tenofovir prodrug, tenofovir disoproxil fumarate, tenofovir alafenamide is stable in plasma and then rapidly converted into tenofovir once inside cells.
  
  
  METHODS
  The pharmacokinetics, safety and antiviral activity of 40 or 120 mg of tenofovir alafenamide compared with 300 mg of tenofovir disoproxil fumarate when administered as monotherapy once daily for 14 days in HIV-1-infected, treatment-naive subjects was studied.
  
  
  RESULTS
  Administration of 40 mg of tenofovir alafenamide for 14 days resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic exposures (AUC0-t, 383 versus 1810 ng · h/mL) compared with subjects who received tenofovir disoproxil fumarate. There were higher intracellular tenofovir concentrations within peripheral blood mononuclear cells with both 40 mg of tenofovir alafenamide (8.2 μM) and 120 mg of tenofovir alafenamide (16.9 μM) compared with 300 mg of tenofovir disoproxil fumarate (0.9 μM). The most commonly observed adverse events were headache, nausea and flatulence, which occurred similarly across the three groups. After 14 days, the mean changes in HIV-1 RNA were -0.94 log₁₀copies/mL for the tenofovir disoproxil fumarate group, -1.57 log₁₀ copies/mL for the 40 mg of tenofovir alafenamide group and -1.71 log₁₀ copies/mL for the 120 mg of tenofovir alafenamide group. The mean first-phase HIV-1 RNA decay slopes were -0.36, -0.63 and -0.64 for the tenofovir disoproxil fumarate group, the 40 mg of tenofovir alafenamide group and the 120 mg of tenofovir alafenamide group, respectively. No resistance mutations to either tenofovir alafenamide or tenofovir disoproxil fumarate were detected.
  
  
  CONCLUSIONS
  Tenofovir alafenamide, a new once-daily oral prodrug of tenofovir, showed more potent anti-HIV-1 activity and higher intracellular tenofovir levels compared with tenofovir disoproxil fumarate, while maintaining lower plasma tenofovir exposure at 40 mg with good tolerability over 14 days of monotherapy.
authors: Aaron Diamond AIDS Research Center, The Rockefeller University Hospital, New York, NY, USA.
authors: Martin
authors: M
authors: Markowitz
authors: Andrew
authors: A
authors: Zolopa
authors: Kathleen
authors: K
authors: Squires
authors: Peter
authors: P
authors: Ruane
authors: Dion
authors: D
authors: Coakley
authors: Brian
authors: B
authors: Kearney
authors: Lijie
authors: L
authors: Zhong
authors: Michael
authors: M
authors: Wulfsohn
authors: Michael D
authors: MD
authors: Miller
authors: William A
authors: WA
authors: Lee
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000409:Alanine; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000068698:Tenofovir / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine
keywords: NRTIs; antiretroviral therapy; nucleotide reverse transcriptase inhibitors