• 20
    Nov
  • Atazanavir and Acid-Lowering Therapy: RESULTS

The search yielded 200 articles, but only 14 met the inclusion criteria (Table 1): 1 prospective study conducted in HIV-positive patients, 5 prospective studies conducted in healthy volunteers, 4 chart reviews involving HIV-positive patients, and 4 case reports.

Prospective Studies

Only 1 prospective trial evaluating HIV-infected individuals has been published to date. Ninety-two patients were enrolled in this prospective open-label study comparing plasma trough concentrations (Cmia) of atazanavir in HIV-infected patients receiving this drug 300 mg with ritonavir 100 mg daily with or without a PPI. Patients were interviewed after undergoing at least 1 week of antiretroviral therapy to determine whether they were taking any acid-lowering therapy and the timing of their most recent dose of atazanavir and rito- navir. Only Cmn values measured 24 ±4 h after the most recent doses were evaluated. A total of 13 patients were taking a PPI. Of these, 9 were taking omeprazole 20 mg daily, 1 was taking omeprazole 40 mg daily, and 3 were taking rabeprazole 20 mg daily. No difference in the median plasma atazanavir Cmin was observed between the 13 patients taking a PPI (median 551 ng/mL, range 203-1976 ng/mL) and the 79 patients not taking a PPI (median 469 ng/mL, range 65-1944 ng/mL) (p = 0.86). The authors did not report whether patient compliance with prescribed therapy was assessed.
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Table 1. Studies Included in an Analysis of Potential Interactions between Atanazavir and Acid-Lowering Agents


Supports or Refutes
Drug Interaction


Reference


Subjects


Acid-Lowering
Agent(s)


Pharmacokinetic
Interaction


Clinically Relevant
Interaction


Prospective,
open-label studies


Guiard-Schmid et al.


92
HIV patients receiving
atazanavir
300
mg/day and ritonavir
100 mg/day
without (n
= 79)
or with (n
= 13) PPI



PPI: omeprazole 20 or
40 mg/day
(n
= 10)
or rabeprazole
20 mg/day
(n
= 3)


Refutes


NA


Agarwala et al.



Healthy volunteers (n
= 48)
receiving atazanavir 300 or 400 mg/day + ritonavir

100 mg/day
with PPI, with or without cola



PPI: omeprazole
40 mg/day


Supports


NA


Prospective,
randomized, open-label studies


Agarwala et al.,



Healthy volunteers
(n
= 64)


Famotidine 40 mg bid


Supports when
famotidine


NA



part 1



receiving famotidine and randomized
to 1 of 4 treatment arms (atazanavir 400 mg/day; atazanavir

400 mg/day
+
cola; atazanavir
400
mg/day temporally separated from
famotidine; atazanavir
300
mg/day +
ritonavir
100
mg/day)


and atazanavir
administered simultaneously; refutes when doses of famotidine and
atazanavir spaced temporally


Agarwala et al.,


Healthy volunteers


Famotidine 40 mg bid


Supports when
famotidine


NA



part 2




(n
= 48) receiving
famotidine and randomized to 1 of 3 treatment arms (atazanavir

300 mg/day
+
ritonavir
100
mg/day; atazanavir
300 mg/day
+
ritonavir
100
mg/day +
cola; atazanavir
400 mg/day
+
ritonavir
100
mg/day)



administered with atazanavir and
ritonavir; AUC and Cmin values maintained with higher doses of
atazanavir
(400
mg) or ritonavir
(100 mg)


Agarwala et al.



Healthy volunteers
(n = 48) receiving
omeprazole PLUS one of the following: atazanavir

400 mg/day
OR atazanavir
400
mg/day with cola OR atazanavir
300
mg/day +
ritonavir
100 mg/day



PPI: omeprazole 40 mg (given
2 h before
atazanavir or ritonavir)


Supports


NA


Prospective,
open-label, crossover studies


Luber et al.



Healthy volunteers (n
= 19)
receiving atazanavir
300
mg/day with ritonavir
100 mg/day
(given in the morning) with or without PPI



PPI: omeprazole
20 mg/day,
given in the evening


Supports


NA


Tomilo et al.*



Healthy volunteers (n
= 10)
receiving a single dose of atazanavir 400 mg (with or without
lansoprazole)


PPI: lansoprazole 60 mg
(2 doses)


Supports


NA

Agarwala and others have presented 3 abstracts evaluating the effects of acid-lowering agents on the pharmacokinetics of atazanavir in healthy subjects. In one abstract, Agarwala and others reported the effects of famotidine 40 mg twice daily on the pharmacokinetics of atazanavir in the presence and absence of ritonavir. In the first part of this study, healthy adults were given atazanavir 400 mg daily for 6 days and then were randomly assigned to 1 of 4 treatment arms (n = 16 for each arm): atazanavir 400 mg daily and famotidine for 6 days; atazanavir 400 mg daily, famotidine, and cola for 6 days; atazanavir 400 mg daily, administered 10 h from the morning famotidine dose and 2 h from the evening famotidine dose for 6 days; or atazanavir 300 mg daily, ritonavir 100 mg daily, and famotidine for 10 days. Other than in the third treatment group, atazanavir and famotidine were administered at the same time. In the second part of the study, healthy subjects were given atazanavir 300 mg and ritonavir 100 mg daily for 10 days and then were randomly assigned to 1 of 3 treatment groups (n = 16 for each arm): atazanavir 300 mg with ritonavir 100 mg daily and famotidine; atazanavir 300 mg with ritonavir 100 mg daily, famotidine, and cola; or atazanavir 400 mg with ritonavir 100 mg daily and famotidine. All doses of famotidine were coadministered with atazanavir. Treatment was continued for 10 days in each arm. In the first part of the study, the area under the curve (AUC) for atazanavir decreased to 41% and Cm,n decreased to 42% of their original values when famotidine was added; the investigators did not indicate whether these decreases were statistically significant. When the administration of famotidine was temporally spaced from the administration of atazanavir, the AUC and Cm,n values were similar to those obtained with atazanavir 400 mg daily alone. In the second part of the study, when pharmacokinetic values were compared with those for subjects who received atazanavir 300 mg with ritonavir 100 mg daily, the addition of famotidine reduced the AUC for atazanavir to 18% and the Cm,n to 28% of their original values. As before, the investigators did not indicate whether these decreases were statistically significant. When famotidine was added to a higher dose of atazanavir (400 mg daily) given with ritonavir 100 mg daily, the AUC and Cmm values were similar to those obtained with atazanavir 300 mg daily plus ritonavir 100 mg daily. In both parts of this study, the addition of cola did not mitigate the pharmacokinetic effects of famotidine on atazanavir. discount tadalafil

The second abstract, presented in 2005 by Agarwala and others, described the pharmacokinetic interaction between atazanavir and omeprazole. Forty-eight healthy subjects received atazanavir 400 mg daily for 6 days and were then randomly assigned to receive either atazanavir 400 mg plus omeprazole 40 mg daily for 6 days; atazanavir 400 mg and omeprazole 40 mg daily with cola for 6 days; or atazanavir 300 mg with ritonavir 100 mg daily and omeprazole 40 mg daily for 10 days. For the subjects who received atazanavir without ritonavir or cola, the omeprazole was given 2 h after the dose of atazanavir on the first day of the study only. The ratios of the geometric means (90% confidence intervals [CIs]) for the comparison between subjects who received atazanavir 400 mg and omeprazole 40 mg daily (for 6 days) and those who received only atazanavir 400 mg daily (also for 6 days) were 0.06 (0.05-0.07) for AUC and 0.05 (0.03-0.07) for Cmin, corresponding to a 94% reduction in AUC and a 95% reduction in Cmm. The ratios of the geometric means (90% CIs) for the comparison between subjects who received atazanavir 300 mg with ritonavir 100 mg daily and omeprazole 40 mg daily (for 10 days) and those who received only atazanavir 400 mg daily (for 6 days) were 0.50 (0.42-0.60) for AUC and 1.23 (1.00-1.52) for Сшт, corresponding to a 50% reduction in AUC and a 23% increase in СШш.

A third abstract by the same group described the pharmacokinetic effect of omeprazole on patients receiving atazanavir coadministered with ritonavir. Forty- eight healthy subjects received atazanavir 300 mg with ritonavir 100 mg daily for 10 days. The subjects were then randomly assigned to receive either atazanavir 300 mg with ritonavir 100 mg and omeprazole 40 mg daily (n = 16); atazanavir 300 mg with ritonavir 100 mg daily, omeprazole 40 mg daily, and cola (n = 16); or atazanavir 400 mg with ritonavir 100 mg and omeprazole 40 mg daily (n = 16) for the next 10 days. The omeprazole was administered in the morning, after the patient had fasted and 2 h before the atazanavir and ritonavir. Serial blood samples were collected on days 10 and 20. All three arms showed a decrease in atazanavir exposure when omeprazole was added, as indicated by the maximum concentration (Cmax), the AUC, and Cmm. The ratios of the geometric means (90% CIs) for the subjects who received atazanavir 300 mg with ritonavir 100 mg and omeprazole 40 mg daily were 0.28 (0.24-0.32) for СШх, 0.24 (0.21-0.27) for AUC, and 0.21 (0.18-0.25) for СШт. For the subjects who received atazanavir 300 mg with ritonavir 100 mg daily, omeprazole 40 mg daily, and cola, the ratios of geometric means (90% CIs) were 0.34 (0.29-0.39) for Cmax, 0.30 (0.27-0.34) for AUC, and 0.24 (0.20-0.29) for СШт. For the group who received atazanavir 400 mg with ritonavir 100 mg and omeprazole 40 mg daily, the ratios of geometric means (90% CIs) were 0.44 (0.38-0.51) for Cmax, 0.39 (0.35-0.45) for AUC, and 0.31 (0.26-0.37) for Cm,n.
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Another study, presented in abstract form by Luber and others, involved 19 healthy adult volunteers who were given atazanavir 300 mg with ritonavir 100 mg daily in the morning alone or in combination with omeprazole 20 mg daily, the latter being given in the evening. Phar- macokinetic analysis was performed before and 7 days after initiation of omeprazole. The pharmacokinetics of atazanavir were affected as follows: Cmin was reduced by 27%, Cmax was reduced by 33%, and the AUC0 -24 h was reduced by 27%. The statistical significance of the results was not reported.

In a single-dose, open-label, 2-phase, crossover study involving 10 healthy adults, Tomilo and others investigated the effect of lansoprazole 60 mg on the pharmacokinetics of atazanavir 400 mg. In the first phase of the study, serum concentrations of atazanavir were measured after a single oral dose of 400 mg. In the second phase, subjects received 2 doses of lansoprazole, on the day before and the day of sample collection when a single oral dose of atazanavir 400 mg was given. For 9 of the 10 subjects, 12 sequential blood samples were collected during the 24-h period after drug administration. The pharmacokinetic parameters measured included Cmax, time at maximum concentration (T^x), AUC0-24 h, and half-life. Between the first and second phases of the study, there was a 94% reduction in AUC0-24 h (p < 0.01) and a 91% reduction in Cmax (p < 0.01). There was no significant change in T^, and half-life could not be reliably assessed. cialis soft tablets

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