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

Abstract

bAs the risk of tenofovir-associated renal toxicity has been found to be proportional to the drug plasma concentration, our aim was to measure the determinants of tenofovir plasma exposure in HIV-positive patients with normal renal function. A crosssectional analysis was conducted in HIV-positive patients chronically receiving tenofovir-containing highly active antiretroviral therapies (HAARTs). Patients on tenofovir-containing antiretroviral regimens, presenting 22 to 26 h after drug intake, having estimated glomerular filtration rates above 60 ml/min, reporting high adherence to antiretroviral medications (above 95% of the doses), and signing a written informed consent were included. Plasma tenofovir concentrations were measured through a validated high-performance liquid chromatography-mass spectrometry (HPLC/LC-MS) method. The tenofovir trough concentrations in 195 patients (median, 50 ng/ml, and interquartile range, 35 to 77 ng/ml) were significantly associated with the estimated glomerular filtration rate, body mass index, and third-drug class (protease-containing versus protease-sparing regimens) (with the highest exposure in unboosted-atazanavir recipients). The results of multivariate analysis showed that the third-drug class and the weight/creatinine ratio were independent predictors of tenofovir trough concentrations. This cross-sectional study shows that tenofovir trough concentrations are predicted by the weight/creatinine ratio and by the coadministered antiretrovirals, with protease inhibitors (whether boosted or unboosted) being associated with the highest plasma exposure. These data, previously available in healthy subjects or for some drugs only, could be useful for designing strategies to manage tenofovir-associated toxicity, since this toxicity has been reported to be dose dependent.

Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines

“…Plasma TFV concentrations have been described in several studies and PIs have been associated with higher trough concentrations: in this analysis we used 12 h concentrations in order to include the majority of patients (efavirenz-containing regimens are usually ingested at night and patients on such regimens were poorly represented in our previous analysis 14 ). TFV plasma C 12 are similar to what reported in previous studies.…”

“…This difference was based on the observed effect of concomitant drugs administration of TFV trough concentrations in a previous study from our group. 14 Baseline characteristics were tested for correlation to plasma and urinary concentrations using the Spearman's test for continuous variables and by the Mann-Whitney (or Kruskal-Wallis if three or more) tests for categorical variables. Associations between genotypes and TFV concentrations were tested by univariate and multivariate stepwise linear regression analyses: SNPs were categorized as dichotomous variables according to the results of univariate analysis.…”

“…9-12 ARV regimens containing both TDF and PIs are associated with higher TFV plasma concentrations (~10-30%), suggesting a role for PIs in decreasing TFV tubular clearance possibly through the functional inhibition of P-glycoprotein (PgP) and MRP efflux transporters inhibition. 13,14 Furthermore, loss of function variants in genes encoding for MRP-2 and MRP-7 have been found to be associated with rise in several tubular toxicity markers. [15][16][17] The proposed mechanism is the 'entrapment' of TFV inside tubular cells (either resulting from genetic-determined and/ or pharmacological inhibition of efflux hypo-functioning transporters at the urinary side) with subsequent mitochondrial damage, as also seen in electronic microscopy studies.…”

Pharmacokinetic and pharmacodynamic evaluation of raltegravir and experience from clinical trials in HIV-positive patients

“…In some studies, co-administration of raltegravir with darunavir resulted in a modest decrease in darunavir plasma concentrations that did not appear to be clinically meaningful [24]. It should be highlighted that tenofovir plasma concentrations were slightly reduced with raltegravir (--10 and --13% in AUCs and C 24 ): this may be beneficial given the probable dose-dependent tubular toxicity that has been associated with tenofovir use [25,26].…”

High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors

“…15,22,32 Higher tenofovir plasma concentration was associated with alterations in renal markers (both glomerular and tubular), 33,34 and the highest plasma exposure was associated with the concomitant use of protease inhibitors. 35 However, whether co-administered or not with protease inhibitors, tenofovir was not associated with proteinuria > 300 mg/g in our cohort. In fact, the most common form of TDF-related toxicity is a low level of proteinuria, 27 that is usually reversible after the interruption of the drug.…”