In a combined analysis from several clinical studies, atazanavir/ritonavir 300/100 mg co-administered with tenofovir disoproxil fumarate 300 mg (n=39) was compared to atazanavir/ritonavir 300/100 mg (n=33). Atazanavir AUC, Cmax and Cmin decreased 22%, 16% and 23%, respectively. Coadministration of tenofovir disoproxil fumarate (300 mg once daily) with atazanavir/ritonavir (300 mg/100 mg once daily) was studied in healthy volunteers. Tenofovir-DF AUC, Cmax and Cmin increased 37%, 34% and 29%, respectively. The mechanism of interaction between atazanavir and tenofovir disoproxil fumarate is unknown. The efficacy of Reyataz/ritonavir in combination with tenofovir disoproxil fumarate in treatment-experienced patients has been demonstrated in clinical study 045 and in treatment naive patients in clinical study 138. When coadministered with tenofovir disoproxil fumarate, it is recommended that Reyataz 300 mg be given with ritonavir 100 mg and tenofovir disoproxil fumarate 300 mg (all as a single dose with food). Patients should be closely monitored for tenofovir disoproxil fumarate-associated adverse reactions, including renal disorders. Reyataz given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil.

Tenofovir DF may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir DF in adults, it is recommended that Reyataz 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). Reyataz increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving Reyataz and tenofovir DF should be monitored for tenofovir-associated adverse reactions. Coadministration of tenofovir-DF (300 mg, once daily) with atazanavir (400 mg, once daily) was studied in 34 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 21%, 25% and 40%, respectively. Tenofovir Cmax, AUC and Cmin increased 14%, 24%, and 22%, respectively (n=33). Coadministration of tenofovir-DF (300 mg, once daily) with atazanavir/ritonavir (300 mg/100 mg, once daily) was studied in 12 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 28%, 25% and 23%, respectively (n=10). Tenofovir Cmax, AUC and Cmin increased 34%, 37% and 29%, respectively. Note that similar results were observed in studies where administration of tenofovir DF and Reyataz was separated by 12 hours. Atazanavir 300 mg plus ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg. The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax = 3190 ng/mL, AUC = 34459 ng.h/mL, and Cmin = 491 ng/mL. Study was conducted in HIV-infected individuals.

Coadministration of atazanavir/ritonavir (300/100 mg once daily) and tenofovir-DF (300 mg once daily) decreased atazanavir AUC (25%), Cmax (28%) and Cmin (26%). Tenofovir AUC increased by 37%, Cmax increased by 34% and Cmin increased by 29%. No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir-associated adverse events, including renal disorders. Renal function should be closely monitored.

Coadministration of atazanavir (400 mg once daily for 14 days) and tenofovir-DF (300 mg once daily) to 33 subjects increased tenofovir Cmax (14%), AUC (24%) and Cmin (22%). Atazanavir Cmax, AUC and Cmin decreased by 21%, 25% and 40% respectively. Coadministration of tenofovir-DF and atazanavir/ritonavir (300/100 mg once daily for 42 days) increased tenofovir Cmax, AUC and Cmin by 34%, 37% and 29%, respectively; atazanavir Cmax, AUC and Cmin decreased by 28%, 25%, and 23%, respectively. In HIV-infected patients, the addition of tenofovir-DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. When coadministered with tenofovir-DF, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenofovir-DF should not be coadministered with atazanavir without ritonavir. Patients receiving tenofovir-DF concomitantly with ritonavir-boosted atazanavir should be monitored for tenofovir-associated adverse reactions. Tenofovir-DF should be discontinued in patients who develop tenofovir-associated adverse reactions. 

Coadministration of tenofovir-DF (300 mg, once daily) with atazanavir/ritonavir (300 mg/100 mg, once daily, with NRTIs) was studied in 20 HIV positive patients. Atazanavir Cmin decreased 3% and Cmax and AUC increased 7% and 8%, respectively. These differences are not statistically significant. 

A study was performed in healthy volunteers to determine whether increasing ATV/RTV from 300/100 mg to 400/100 mg once daily with TDF or maintaining the standard dose but separating administration of TDF by 12 h, could overcome the 25% decrease in ATV exposure previously seen when coadministered with TDF. Relative to ATV/RTV 300/100, simultaneous administration of ATV/RTV 400/100 resulted in increases in ATV AUC and Cmin of 38% and 33% respectively. TDF AUC and Cmin increased by 55% and 70% respectively. Maintaining the standard dose, but separating administration by 12 h, resulted in an 11% decrease in ATV AUC and a 20% decrease in Cmin. TDF AUC and Cmin increased by 37% and 29% respectively. RTV exposure was comparable across treatments. Due to the increases in ATV and higher TDF exposures, coadministration of ATV/RTV 400/100 mg with TDF is not recommended. Separation of ATV/RTV 300/100 mg and TDF doses are not expected to offer any additional clinical advantage over simultaneous administration. 

The pharmacokinetics of TDF (300 mg once daily), when given with ATV/RTV (300/100 mg once daily), were assessed in a substudy of the Puzzle2-ANRS 107 trial. Full PK profiles were determined in 10 patients: median (range) TDF Cmax, Cmin and AUC were 234 (121-855) ng/ml, 45 (23-215) ng/ml and 2253 (1305-11285) ng/ml.h respectively. Trough concentrations at weeks 6, 10, 18 and 26 were 58, 64, 53 and 57 ng/ml respectively (n=32-38). Tenofovir pharmacokinetic parameters were comparable to historical data obtained from healthy and HIV+ subjects, suggesting that tenofovir exposure is not substantially altered when coadministered with atazanavir/ritonavir. 

Coadministration of tenofovir-DF (300 mg, once daily) with atazanavir/ritonavir (300 mg/100 mg, once daily) was studied in 10 male HIV positive patients. Atazanavir Cmax, Cmin and AUC decreased ~34%, ~33% and ~27%, respectively. The decrease in AUC is the only PK parameter which reached significance. No significant correlation between the decreased atazanavir exposure and the viral response was seen.

Steady-state atazanavir concentrations were assessed in HIV+ patients taking atazanavir/ritonavir (300/100 mg once daily) with and without tenofovir-DF and/or nevirapine. No significant difference was observed in atazanavir concentrations for patients taking atazanavir/ritonavir alone and those taking tenofovir-DF. There was a trend towards decreased atazanavir concentrations for patients co-dosed with nevirapine (with or without tenofovir). These results from a clinical setting suggest that ritonavir boosting of atazanavir reduces the interaction with tenofovir; however, it may not overcome interactions with nevirapine. 

The pharmacokinetics of atazanavir/ritonavir (300/100 mg once daily) with tenofovir-DF (300 mg once daily) were investigated in 10 HIV+ patients. After the addition of tenofovir-DF, both atazanavir and ritonavir exposure were reduced. Atazanavir Cmax decreased from 5233 ± 3033 to 3443 ± 1412 ng/ml (mean ± SD), AUC decreased from 53761 ± 35255 to 39276 ± 23034 ng/ml.h, and Cmin decreased from 862 ± 838 to 577 ± 367 ng/ml.