title: Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients.
abstract: Recent work has demonstrated the existence of a systemic interaction between didanosine (ddI) and tenofovir disoproxyl fumarate (TDF) that leads to a significant increase in plasma ddI levels when coadministered with TDF (40 to 50% increase). These two drugs are, respectively, nucleoside and nucleotide analogues of adenosine and efficiently inhibit the human immunodeficiency virus (HIV) reverse transcriptase when transformed to their triphosphate moieties in the intracellular (IC) medium (ddA-TP and TFV-DP, respectively). Since ddI and TDF partly share the same IC metabolic pathway leading to the active triphosphates, we investigated a putative IC interaction. We used high-performance liquid chromatography-tandem mass spectrometry techniques to determine ddA-TP and TFV-DP IC levels in HIV-infected patients cotreated with both drugs, in comparison with patients treated with just one of the two drugs. These measurements revealed no significant differences in IC levels of the corresponding triphosphates when ddI (250 mg, once a day [QD]) was coadministered with TDF (300 mg, QD) compared to ddI 400 mg (QD) administered without TDF, thus supporting the dose adaptation proposed for this combination. However, we observed that both ddA-TP and TFV-DP have very long IC half-lives, resulting in unusual IC pharmacokinetic profiles with no significant changes in triphosphate concentrations between two dosings. In the case of TFV-DP, this t(1/2) of elimination was roughly estimated to be 180 h (7.5 days). This characteristic is certainly interesting in terms of efficacy but could have some drawbacks in terms of virus resistance for patients discontinuing these drugs.
authors.affiliation: CEA, Service de Pharmacologie et d'Immunologie, DSV/DRM, CEA/Saclay, 91191 Gif sur Yvette cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.forename: Eugènia
authors.initials: E
authors.lastname: Negredo
authors.forename: Henri
authors.initials: H
authors.lastname: Benech
authors.forename: Frédéric
authors.initials: F
authors.lastname: Theodoro
authors.forename: Jordi
authors.initials: J
authors.lastname: Puig
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Grau
authors.forename: Elisabet
authors.initials: E
authors.lastname: García
authors.forename: José
authors.initials: J
authors.lastname: Moltó
authors.forename: Jacques
authors.initials: J
authors.lastname: Grassi
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D002452:Cell Count; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D016049:Didanosine / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008137:Longitudinal Studies; D013058:Mass Spectrometry; D063065:Organophosphonates / Q000493:pharmacokinetics*; D010766:Phosphorylation; D012015:Reference Standards; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine