title: Intracellular nucleotide levels during coadministration of tenofovir disoproxil fumarate and didanosine in HIV-1-infected patients.
abstract: Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.
authors.affiliation: Southwest CARE Center, Santa Fe, New Mexico, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hawkins
authors.forename: Wenoah
authors.initials: W
authors.lastname: Veikley
authors.forename: Lucie
authors.initials: L
authors.lastname: Durand-Gasselin
authors.forename: Darius
authors.initials: D
authors.lastname: Babusis
authors.forename: Y Sunila
authors.initials: YS
authors.lastname: Reddy
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D003838:Deoxyadenine Nucleotides / Q000097:blood; D003848:Deoxyguanine Nucleotides / Q000097:blood; D016049:Didanosine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D054306:Dideoxynucleotides / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009711:Nucleotides / Q000097:blood*; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry; D000068698:Tenofovir; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D003848:Deoxyguanine Nucleotides; D054306:Dideoxynucleotides; D009711:Nucleotides; D063065:Organophosphonates; C037773:2',3'-dideoxyadenosine triphosphate; C029603:deoxyguanosine triphosphate; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine; C026600:2'-deoxyadenosine triphosphate