Coadministration of omeprazole (40 mg, once daily) with atazanavir/ritonavir (400 mg/100 mg, once daily, 2 hours after omeprazole) was studied in healthy volunteers. Atazanavir AUC, Cmax and Cmin decreased 61%, 66% and 65%, respectively. Coadministration of omeprazole (20 mg, once daily) with atazanavir/ritonavir (400 mg/100 mg, once daily, 1 hour after omeprazole) was studied in healthy volunteers. Atazanavir AUC decreased 30% and Cmax and Cmin decreased 31% when compared to atazanavir 300 mg once daily with ritonavir 100 mg once daily. The decrease in AUC, Cmax, and Cmin was not mitigated when an increased dose of Reyataz/ritonavir (400/100 mg once daily) was temporally separated from omeprazole by 12 hours. This decrease in atazanavir exposure might negatively impact the efficacy of atazanavir. The mechanism of interaction is decreased solubility of atazanavir as intra-gastric pH increases with proton pump inhibitors. Coadministration of Reyataz with proton pump inhibitors is not recommended. If the combination of Reyataz with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of Reyataz to 400 mg with 100 mg of ritonavir; doses of omeprazole should not exceed 20 mg. Coadministration of Reyataz without ritonavir is not recommended with proton pump inhibitors.

Plasma concentrations of atazanavir were substantially decreased when Reyataz 400 mg or Reyataz 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily in adults, which may result in loss of therapeutic effect and development of resistance. In treatment-naive adult patients: omeprazole should not exceed 20 mg and must be taken approximately 12 hours prior to the Reyataz 300 mg with ritonavir 100 mg dose. In treatment-experienced adult patients: the use of PPIs in treatment-experienced patients receiving Reyataz is not recommended. Coadministration of omeprazole (40 mg once daily) 2 h before atazanavir (400 mg, once daily) was studied in 16 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 96%, 94% and 95%, respectively. When omeprazole (40 mg single dose) was given 2 hours after atazanavir (400 mg once daily), omeprazole Cmax and AUC increased 24% and 45%, respectively (compared to omeprazole alone 2 hours after a light meal, n=16). Coadministration of omeprazole (40 mg, once daily) 2 h before atazanavir/ritonavir (300 mg/100 mg, once daily) was studied in 15 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 72%, 76% and 78%, respectively. Coadministration of omeprazole (20 mg, once daily) with atazanavir/ritonavir (300 mg/100 mg, once daily, 12h after omeprazole) was studied in 13 healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased 39%, 42% and 46%, respectively. Reyataz 300 mg plus ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and Cmin (2.4-fold), with a decrease in Cmax (29%) relative to Reyataz 400 mg once daily in the absence of omeprazole (study days 1–6). Coadministration of omeprazole (20 mg, once daily) with atazanavir/ritonavir (400 mg/100 mg, once daily, 1h after omeprazole) was studied in 14 healthy volunteers. Atazanavir AUC decreased 30% and Cmax and Cmin both decreased 31%. Reyataz 400 mg plus ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and Cmin (3.3-fold), with a decrease in Cmax (26%) relative to Reyataz 400 mg once daily in the absence of omeprazole (study days 1-6).

Coadministration of omeprazole (20 mg, once daily, either in the morning (QAM) or the evening (QPM) with atazanavir/ritonavir (300 mg/100 mg, QPM) was studied in healthy volunteers. Atazanavir Cmax, AUC and Cmin decreased by ~45%, ~35% and ~50%, respectively when the drugs were coadministered simultaneously. Atazanavir Cmax, AUC and Cmin decreased ~39%, ~42% and ~46%, respectively, when the drugs were administered 12 hours apart. The authors conclude that reducing omeprazole doses from 40 mg to 20 mg can mitigate the decrease in atazanavir exposure seen with coadministration.

The effect of a lower dose of omeprazole (20 mg) on the pharmacokinetics of atazanavir/ritonavir (300/100 or 400/100 mg once daily) when given with omeprazole either simultaneously or 12 h apart was studied in groups of HIV- subjects (n=14 per group). When atazanavir was dosed in the evening, giving omeprazole 12 h apart, decreased atazanavir Cmax (39%), AUC (42%) and Cmin (46%); giving omeprazole 12 h apart and increasing atazanavir to 400 mg decreased atazanavir Cmax (29%), AUC (28%) and Cmin (24%). When atazanavir was dosed in the morning, giving omeprazole 1 h prior to atazanavir and increasing atazanavir to 400 mg decreased atazanavir Cmax, AUC and Cmin all by ~30%; giving omeprazole 12 h apart and increasing atazanavir to 400 mg, decreased atazanavir Cmax (20%), AUC (29%) and Cmin (37%). When compared to concentrations obtained with ATV 400 mg alone, all atazanavir + omeprazole combinations resulted in comparable atazanavir AUCs and ~2-fold increases in Cmin. Despite increasing atazanavir to 400 mg, when given with omeprazole atazanavir exposure was decreased by ~30% (relative to 300/100 mg alone) with the effect of omeprazole being similar when given either 1 h before or 12 h apart from ATV.

Atazanavir trough concentrations (24 ± 4 h post dose) were determined in 13 HIV+ patients receiving either atazanavir/ritonavir (300/100mg once daily) with a proton pump inhibitor (omeprazole n=10, rabeprazole n=3) and in 79 HIV+ patients receiving atazanavir/ritonavir alone. Median (range) atazanavir concentrations were 551 (203-1976) ng/ml in the presence of a PPI and 469 (65-1944) ng/ml when given alone.

An interaction study of the pharmacokinetics of atazanavir/ritonavir (300/100 mg once daily given in the morning) and fosamprenavir/ritonavir (1400/200 mg once daily given in the morning) alone and in combination with 20 mg of omeprazole once daily (given in the evening) was performed in 19 healthy adult volunteers. Full 24-hour pharmacokinetic analysis was performed before and 7 days into the omeprazole treatment. Each study subject took both PIs under the same conditions and therefore each subject acted as their own control. The addition of 20 mg omeprazole as an evening regimen did not affect amprenavir pharmacokinetics with geometric mean ratios (GMRs) for Cmin, Cmax, and AUC24 all close to 1. In contrast, atazanavir pharmacokinetics were significantly altered with reductions of 27%, 33% and 27% for Cmin, Cmax, and AUC respectively. 

The effect of the proton pump omeprazole (40 mg once daily) on the pharmacokinetics of atazanavir/ritonavir (300/100 mg alone or with cola, or 400/100 mg alone) was investigated in healthy subjects. Atazanavir exposures were substantially reduced with omeprazole in all three groups: Cmin decreased from 1366 ng/ml to 285, 330, 423 ng/ml, Cmax decreased from 5460 to 1522, 1840, 2388 ng/ml and AUC decreased from 60797 to 14605, 18325, 23968 ng/ml.h. Omeprazole exposures were generally comparable to literature values and were similar between groups. Proton pump inhibitors should not be used in patients on atazanavir/ritonavir regimens when atazanavir exposures similar to a boosted atazanavir regimen are required. 

Trough atazanavir concentrations were available in 15 patients receiving a proton pump inhibitor (PPI) and 19 patients receiving an H2 receptor antagonist (H2). The mean atazanavir trough concentration in the PPI group was 0.65 µg/ml (range <0.05 to 1.85 µg/ml) compared to 1.12 µg/ml (range <0.05 to 3.17 µg/ml) in the H2 group. Concentrations were below target (0.27 µg/ml) in 6/15 in the PPI group, even though 5 of these were receiving boosted atazanavir. Inadequate levels were observed in 4/20 in the H2 group, 2 of whom were receiving boosted atazanavir. These results suggest a negative effect of proton pump inhibitors and H2 receptor antagonists on atazanavir concentrations and that boosting with ritonavir does not ensure adequate concentrations. Further study of this important issue is warranted.