Since only limited data on tenofovir exposure in patients are available (8) and in order to better understand the relationship between specific antiretrovirals and the drug pharmacokinetic profile, we carried out a cross-sectional pharmacokinetic survey in patients under successful and renally safe (estimated creatinine clearance [eCLCR], 60 ml/min) chronic TDF administration. (Some of the data in the manuscript were presented as a poster at Buparvaquone the 18th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 5 to 8 March 2012 [9].) MATERIALS AND METHODS Patients on TDF-containing antiretroviral regimens were consecutively enrolled at the Department of Infectious Diseases of the University of Torino and at the Amedeo di Savoia Hospital, Torino, Italy, between September 2010 and January 2011. the highest exposure in unboosted-atazanavir recipients). The results of multivariate analysis showed that this third-drug class and the weight/creatinine ratio were impartial 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. INTRODUCTION Although the majority of successful highly active antiretroviral therapy (HAART)-treated HIV-positive patients are taking tenofovir disoproxil fumarate (TDF) as part of their nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI] backbone, the drug is being increasingly associated with renal tubular dysfunction (1C3). While in clinical reports, the impact of TDF on renal function is mostly described in terms of decrease of estimated glomerular filtration rate (GFR), TDF appears unlikely to directly harm any glomerular structure and its effect on GFR estimation depends upon the decreased creatinine secretion that is secondary to tubular Mmp2 dysfunction (3). In four impartial clinical studies, TDF pharmacokinetic (PK) exposure was found to be associated with alterations in a series of renal function markers, both glomerular and tubular (4C7). According to drug-drug conversation studies of healthy volunteers, the PK exposure of tenofovir seems to be rather sensitive to the choice of companion drugs, which suggests that, depending on the specific HAART regimen, its impact on tubular function may also vary. In agreement with this assumption, in large-scale cohort studies, the likelihood of TDF-associated renal dysfunction was found to vary depending upon the antiretrovirals being concurrently administered, with ritonavir-boosted protease inhibitors (PIs/r) being associated with the highest risk (3). Since only limited data on tenofovir exposure in patients are available (8) and in order to better understand the relationship between specific antiretrovirals and the drug pharmacokinetic profile, we carried out a cross-sectional pharmacokinetic survey in patients under successful and renally safe (estimated creatinine clearance [eCLCR], 60 ml/min) chronic TDF administration. (Some of the data in the manuscript were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 5 to 8 March 2012 [9].) MATERIALS AND METHODS Patients on TDF-containing antiretroviral regimens were consecutively enrolled at the Department of Infectious Diseases of the University of Torino and at the Amedeo di Savoia Hospital, Torino, Italy, between September 2010 and January 2011. The protocol was approved by the local ethics committee. Patients were included if they had taken TDF 22 to 26 h before, reported high adherence to antiretroviral medications (above 95% of the doses), presented no concomitant renal disease, and signed a written informed consent. Patients diagnosed with chronic kidney Buparvaquone disease (defined by estimated creatinine clearance below 60 ml/min), on hemodialysis, or affected by diabetes mellitus were excluded from this study. Tenofovir trough concentrations were measured through a validated high-performance liquid chromatographyCmass spectrometry (HPLC/LC-MS) method with a limit of detection of 2 ng/ml (10). eCLCR was calculated using the Cockroft-Gault formula. The results are expressed as median values and interquartile ranges; nonparametric assessments (Spearman, Mann-Whitney, and Kruskal-Wallis) were used for all the analyses (comparisons and correlations), while a multivariate linear regression analysis was used to evaluate the effects of several covariates (with a value of 0.20 at bivariate analysis) on tenofovir plasma exposure. RESULTS One hundred ninety-five adult HIV-positive patients (68.2% male) were enrolled in this study; they were mainly of Caucasian ethnicity (166 [85.1%]). The median values and interquartile ranges for age, body mass index.Calcagno A, Gonzalez de Requena D, Simiele M, D’Avolio A, Tettoni MC, Salassa B, Orofino G, Libanore V, Di Perri G, Bonora S. 2012. inhibitors (whether boosted or unboosted) being associated with the highest plasma exposure. These data, previously available in healthy subjects or for some Buparvaquone drugs only, could be useful for designing strategies to manage tenofovir-associated toxicity, since this toxicity has been reported to be dose dependent. INTRODUCTION Although the majority of successful highly active antiretroviral therapy (HAART)-treated HIV-positive patients are taking tenofovir disoproxil fumarate (TDF) as part of their nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI] backbone, the drug is being increasingly associated with renal tubular dysfunction (1C3). While in clinical reports, the impact of TDF on renal function is mostly described in terms of decrease of estimated glomerular filtration rate (GFR), TDF appears unlikely to directly harm any glomerular structure and its effect on GFR estimation depends upon the decreased creatinine secretion that is secondary to tubular dysfunction (3). In four impartial clinical studies, TDF pharmacokinetic (PK) exposure was found to be associated with alterations in a series of renal function markers, both glomerular and tubular (4C7). According to drug-drug conversation studies of healthy volunteers, the PK exposure of tenofovir seems to be rather sensitive to the choice of companion drugs, which suggests that, depending on the specific HAART regimen, its impact on tubular function may also vary. In agreement with this assumption, in large-scale cohort studies, the likelihood of TDF-associated renal dysfunction was found to vary depending upon the antiretrovirals being concurrently administered, with ritonavir-boosted protease inhibitors (PIs/r) being associated with the highest risk (3). Since only limited data on tenofovir exposure in patients are available (8) and in order to better understand the relationship between specific antiretrovirals and the drug pharmacokinetic profile, we carried out a cross-sectional pharmacokinetic survey in patients under successful and renally safe (estimated creatinine clearance [eCLCR], 60 Buparvaquone ml/min) chronic TDF administration. (Some of the data in the manuscript were presented as a poster at the 18th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 5 to 8 March 2012 [9].) MATERIALS AND METHODS Patients on TDF-containing antiretroviral regimens were consecutively enrolled at the Department of Infectious Diseases of the University of Torino and at the Amedeo di Savoia Hospital, Torino, Italy, between September 2010 and January 2011. The protocol was approved by the local ethics committee. Patients were included if they had taken TDF 22 to 26 h before, reported high adherence to antiretroviral medications (above 95% of the doses), presented no concomitant renal disease, and signed a written informed consent. Patients diagnosed with chronic kidney disease (defined by estimated creatinine clearance below 60 ml/min), on hemodialysis, or affected by diabetes mellitus were excluded from this study. Tenofovir trough concentrations were measured through a validated high-performance liquid chromatographyCmass spectrometry (HPLC/LC-MS) method with a limit of detection of 2 ng/ml (10). eCLCR was calculated using the Cockroft-Gault formula. The results are expressed as median values and interquartile ranges; nonparametric assessments (Spearman, Mann-Whitney, and Kruskal-Wallis) were used for all the analyses (comparisons and correlations), while a multivariate linear regression analysis was used to evaluate the effects of several covariates (with a value of 0.20 at bivariate analysis) on tenofovir plasma exposure. RESULTS One hundred ninety-five adult HIV-positive patients (68.2% male) were enrolled in this study; they were mainly of Caucasian ethnicity (166 [85.1%]). The median values and interquartile ranges for age, body mass index (BMI), plasma creatinine, and eCLCR were 45 years (39 to 50), 23.1 kg/m2 (21.1 to 25.8), 0.96 mg/dl (0.84 to 1 1.08), and 84.4 ml/min (70.2 to 102.9). Patients were cotreated with unboosted atazanavir (ATV) (34 patients [17.4%]), with a boosted protease inhibitor (118 patients [60.5%]; 54 patients on ATV/ritonavir [ATV/r], 30 on lopinavir/ritonavir [LPV/r], and 23 on darunavir/ritonavir [DRV/r]), with nonnucleoside transcriptase inhibitors (NNRTIs) (32 patients [16.4%];16 on nevirapine [NVP] and 13 on efavirenz [EFV]), and with raltegravir (11 patients [5.6%]). The demographic and treatment characteristics of the study participants are summarized in Table 1, stratified by third-drug class. Table 1 Demographic and clinical characteristics value= 195)341183211Gender (male)20 (58.8)84 (71.2)23 (71.9)6 (54.5)0.56Ethnicity (Caucasian)27 (79.4)106 (89.8)24 (75)9.