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Session 113 Poster Abstracts
Pharmacology of Protease Inhibitors
Wednesday, 1:30 - 3:30 pm
Hall A


658
Pharmacokinetic Effect of Omeprazole on Atazanavir Co-administered with Ritonavir in Healthy Subjects
Sangeeta Agarwala*, K Gray, Y Wang, and D Grasela
Bristol-Myers Squibb, Princeton, NJ, USA

Background:  Atazanavir (ATV) is a potent, once-daily protease inhibitor with comparable clinical efficacy to standard of care in antiretroviral naive patients and, when boosted with ritonavir (RTV), to lopinavir (LPV)/RTV in treatment experienced patients. In vitro data has shown that ATV exhibits pH dependent solubility. Consequently, the absorption of ATV is likely to decrease at higher pH values. Proton pump inhibitors (PPI) such as OMP suppress acid secretion and increase gastric pH. The objective of this study was to evaluate the PK effect of omeprazole (OMP) on ATV co-administered with RTV.

Methods:  Healthy subjects (n = 48) received 300/100 mg ATV/RTV daily in an open-label study for 10 days. The subjects were then randomized into 3 equal groups and for the next 10 days, 16 subjects each received:  300/100 mg ATV/RTV+40 mg OMP daily; 300/100 mg ATV/RTV+40 mg OMP daily + cola; or  400/100 mg ATV/RTV+40 mg OMP daily. ATV/RTV was administered with a light meal and OMP was administered after the patient had fasted 2 hours before ATV/RTV in the morning. Serial blood samples were collected for pharmacokinetic profiles on days 10 and 20.

Results:  Geometric mean (CV%) and ratio of the geometric means (90% confidence intervals, CI) for the pharmacokinetic parameters of ATV generated from a general linear model are shown. ATV exposures were substantially reduced on co-administration of OMP. OMP exposures were generally comparable to literature values and exposures overlapped across treatments. No new or unexpected adverse effects attributed to study drug were noted.

 

Parameter

Day 10

Group

Day 20

Ratio (90% CI)

Cmax

(ng/mL)

5459.7

A

B

C

1522.1

1839.7

2387.9

0.28           (0.24, 0.32)

0.34           (0.29, 0.39)

0.44           (0.38, 0.51)

AUC(TAU)

(ng·h/mL)

60796.5

A

B

C

14605.4

18324.6

23967.9

0.24           (0.21, 0.27)

0.30           (0.27, 0.34)

0.39           (0.35, 0.45)

Cmin

(ng/mL)

1366.2

A

B

C

285.1

330.4

423.0

0.21           (0.18, 0.25)

0.24           (0.20, 0.29)

0.31           (0.26, 0.37)

Keywords: atazanavir; omeprazole; ritonavir