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Antimicrobial Agents and Chemotherapy, May 2005, p. 1907-1914, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1907-1914.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Measurement of Intracellular Didanosine and Tenofovir Phosphorylated Metabolites and Possible Interaction of the Two Drugs in Human Immunodeficiency Virus-Infected Patients

Alain Pruvost,1 Eugènia Negredo,2 Henri Benech,1 Frédéric Theodoro,1 Jordi Puig,2 Eulàlia Grau,2 Elisabet García,2 José Moltó,2 Jacques Grassi,1* and Bonaventura Clotet2

CEA, Service de Pharmacologie et d'Immunologie, DSV/DRM, CEA/Saclay, 91191 Gif sur Yvette cedex, France,1 Lluita contra la SIDA and "Irsicaixa" Foundations, Germans Trias i Pujol Hospital, Badalona, Barcelona, Spain2

Received 31 July 2004/ Returned for modification 12 October 2004/ Accepted 3 January 2005

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 t1/2 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.

* Corresponding author. Mailing address: Service de Pharmacologie et d'Immunologie, bâtiment 136, CEA/Saclay, 91191 Gif sur Yvette cedex, France. Phone: 33-6-1-73-99-57-85. Fax: 33-1-69-08-59-07. E-mail: jacques.grassi{at}cea.fr.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1907-1914, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1907-1914.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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