Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, May 2009, p. 1937-1943, Vol. 53, No. 5
0066-4804/09/$08.00+0 doi:10.1128/AAC.01064-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir
Alain Pruvost,1*
Eugènia Negredo,2
Frédéric Théodoro,1
Jordi Puig,2
Mikaël Levi,1,3
Rafaela Ayen,4
Jacques Grassi,1 and
Bonaventura Clotet2,4
CEA, iBiTecS, SPI, Laboratoire d'Etude du Métabolisme des Médicaments, Gif sur Yvette, F-91191,1 SPI-BIO, Parc d'Activité du Pas du Lac, 10 bis avenue Ampère, F-78180 Montigny le Bretonneux, France,3 Lluita contra la SIDA Foundation,2 Irsicaixa Foundation, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain4
Received 7 August 2008/ Returned for modification 20 October 2008/ Accepted 23 February 2009
Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC0-4), the maximum concentration of the drug (Cmax), and the residual concentration of the drug at the end of the dosing interval (Ctrough) for plasma and the AUC0-4 and Ctrough for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC0-4 was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and Ctrough values for women.
* Corresponding author. Mailing address: CEA, IBiTec-S, Service de Pharmacologie et d'Immunoanalyse, PC no. 18, F-91191 Gif sur Yvette, France. Phone: 33 1 69081312. Fax: 33 1 69085907. E-mail: alain.pruvost{at}cea.fr
Published ahead of print on 9 March 2009.
Antimicrobial Agents and Chemotherapy, May 2009, p. 1937-1943, Vol. 53, No. 5
0066-4804/09/$08.00+0 doi:10.1128/AAC.01064-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»