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

Abstract

Tenofovir is a nucleotide analogue used as a combination therapy with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. To be active, tenofovir needs to be converted at the intracellular level to tenofovir diphosphate, which inhibits the viral reverse transcriptase (10). A pharmacokinetic study performed after intravenous administrations of tenofovir in HIV-infected adults (5) has shown that 70 to 80% of the dose was recovered unchanged in urine and that tubular secretion was an important pathway for tenofovir clearance. A significant increase in tenofovir exposure was also demonstrated in adult patients with creatinine clearance (CL CR ) less than 50 ml/min, which required a decrease in tenofovir dosage regimen for this subpopulation (10). For adult patients with CL CR greater than 50 ml/min, the same dosage regimen of 300 mg once a day (QD) of tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir, is recommended. However, the influence of renal function on tenofovir exposure has still not been studied in patients with CL CR greater than 50 ml/min.Thus, in order to evaluate whether a dose adjustment based on renal function could be considered for tenofovir therapy, even in patients receiving the recommended 300-mg QD dose, the influence of the renal function on tenofovir pharmacokinetics was investigated using a population approach performed retrospectively on routine therapeutic drug monitoring data. MATERIALS AND METHODSPatients and treatment. The population comprised adult patients receiving TDF, as 300-mg tablets equivalent to 245 mg of tenofovir, at its recommended 300-mg QD dose for the treatment of HIV infection and monitored according to the plasma concentrations of antiretroviral drugs on a routine basis. For each patient, time elapsed between administration and sampling times, gender, body weight (BW), and age were carefully recorded, as well as combined treatments, particularly antiretroviral drugs. Corresponding serum creatinine (S CR ), phosphorus concentration, and viral load were obtained from routine monitoring data performed in Cochin-Saint-Vincent-de-Paul Hospital Biochemistry and Virology Departments respectively. Creatinine clearance was calculated for each sample according to the Cockroft-Gault formula (3) and the Jelliffe formula (8).Analytical methods. The tenofovir assay was performed according to a previously published method (9) with a quantification limit, interassay precision, and bias of 0.005 mg/liter, 9.6%, and 11.4%, respectively.Population pharmacokinetic modeling. Concentration-time data were analyzed using the first-order conditional estimation (FOCE) method of the nonlinear mixed effects modeling program NONMEM (2) (version V, level 1.1, double precision). Several structural pharmacokinetic models were investigated. Classical one, two, and three-compartment models were first evaluated. A twocompartment pharmacokinetic model in which the absorption (k a ) and distribution rate (␣) constants are equal was also tried (1...

p16INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects

“…Both TFV and FTC are transporter substrates, and recent work has demonstrated variability in transporter expression can affect intracellular PKs 30. As in previous models of TFV and FTC, creatinine CL is a significant covariate for TFV and FTC plasma CL 31, 32, 33, 34. Age and creatinine CL are correlated, and an independent effect of chronologic age above that of creatinine CL was not observed in either model.…”

Tenofovir Plasma Concentrations According to Companion Drugs: a Cross-Sectional Study of HIV-Positive Patients with Normal Renal Function

“…Our results further support the hypothesis of a tenofovir dose/ concentration-dependent toxicity, since TDF PK exposure was found to vary significantly according to the third antiretroviral being concurrently taken, with a magnitude that reproduces the relative risk of TDF-associated nephrotoxicity according to concurrently administered drugs seen in cohort studies. In looking at TDF concentrations, it must be considered that in the three studies associating higher tenofovir exposures to kidney tubular dysfunction, the mid-dose value (approximately 12 h after drug intake) (4-7) was used, while our plasma samples were taken at 24 h. While other factors were found to influence tenofovir plasma trough concentrations (age, BMI, and eCL CR , including the previously suggested combined parameter weight/plasma creatinine) (12,13), the choice of the third-drug class seems to be the only readily modifiable factor. As was found in EUROSIDA, D:A:D:, and two additional retrospective surveys, (3,(14)(15)(16), the use of boosted PIs together with TDF is associated with the highest risk of renal toxicity, with reduced risk in the case of NNRTI or raltegravir coadministration.…”

Síndrome de Fanconi induzida pelo uso de Tenofovir em pessoa coinfectada HIV-Hepatite B multirresistente

“…A esse respeito, a duração média do tratamento com TDF antes de desenvolver SF, em pessoas suscetíveis a essa complicação, é de 11 meses 6 . No caso relatado, elevação da creatinina plasmática foi notada a partir de 14 meses de uso desse medicamento e a SF foi diagnosticada por meio dos respectivos achados clínicos e laboratoriais, apoiados pelo vínculo epidemiológico direto com o TDF, 22 meses depois da introdução desse medicamento no esquema terapêutico.…”

“…Diante de um caso convencional de SF, a retirada do agente causal é a principal terapêutica para evitar danos renais irreversí-veis [3][4][5][6] . No entanto, essa não foi a opção no caso relatado porque a Hepatite B crônica em tratamento com TDF era resistente a todos os outros agentes farmacológicos respectivamente indicados.…”

“…Entre essas alterações, a perda crônica de fosfato é a que mais tem repercussões clínicas, por favorecer o desenvolvimento de osteomalácia, dor óssea e fraturas [3][4][5][6] .…”