Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy.
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 (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 297 +/- 28.5 [corrected] liters, 848 +/- 209 [corrected] liters, 80 +/- 15 [corrected] liters/h and 50.5 +/- 3.1 [corrected] liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) 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 (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg . h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated.
Jullien
Vincent
V
Service de Pharmacologie Clinique, Hôpital Cochin-Saint-Vincent-de-Paul, 74-82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Vincent.jullien@svp.aphp.fr
Tréluyer
Jean-Marc
JM
Rey
Elisabeth
E
Jaffray
Patrick
P
Krivine
Anne
A
Moachon
Laurence
L
Lillo-Le Louet
Agnès
A
Lescoat
Anne
A
Dupin
Nicolas
N
Salmon
Dominique
D
Pons
Gérard
G
Urien
Saïk
S
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D001499:Bayes Theorem; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine