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Antimicrobial Agents and Chemotherapy, August 2005, p. 3361-3366, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3361-3366.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

Vincent Jullien,1,2,3* Jean-Marc Tréluyer,1,2,3 Elisabeth Rey,1,2,3 Patrick Jaffray,1,2,4 Anne Krivine,1,2,5 Laurence Moachon,1,2,3 Agnès Lillo-Le Louet,1,2,6 Anne Lescoat,1,2,3 Nicolas Dupin,1,2,7 Dominique Salmon,1,2,8 Gérard Pons,1,2,3 and Saïk Urien9

Université Paris-Descartes, Faculté de Médecine,1 Assistance Publique-Hôpitaux de Paris,2 Pharmacologie Clinique,3 Biochimie A,4 Virologie,5 Dermatologie-Vénérologie,7 Médecine Interne, Groupe Hospitalier Cochin-Saint-Vincent-de-Paul, 82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France,8 Pharmacologie Clinique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France,6 Institut National de la Santé et de la Recherche Médicale, 101 rue de Tolbiac, 75654 Paris Cedex 13, France9

Received 1 March 2005/ Returned for modification 22 May 2005/ Accepted 31 May 2005

The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc/F), peripheral distribution volume (Vp/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 534 liters, 1,530 liters, 144 liters/h and 90.9 liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/SCR) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC0-24). In patients without tubular dysfunction, AUC0-24 values markedly decreased from 6.7 to 1.4 mg · h/liter for BW/SCR increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/SCR should be further evaluated.

* Corresponding author. Mailing address: Service de Pharmacologie Clinique, Hôpital Cochin-Saint-Vincent-de-Paul, 74-82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Phone: 33 1 40488209. Fax: 33 1 40488223. E-mail: Vincent.jullien{at}svp.aphp.fr.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3361-3366, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3361-3366.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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