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Session 114
Poster Abstracts Pharmacology: Entry Inhibitors and P-Glycoprotein Friday, 1:30 - 3:30 pm Hall A |
Background: UK-427,857, an antagonist of the CCR5
receptor with potent anti-HIV activity is being developed for the treatment of
HIV infection. A study in HIV + ve subjects, stable
for 3 months on selected common antiretroviral (ARV) therapies, was conducted
to evaluate the effect of these combinations on the pharmacokinetics of a
single oral dose of UK-427,857 300 mg.
Methods: In this study, 4 cohorts of subjects on the following combination
therapies were recruited:
Cohort 1 -Efavirenz+Combivir
(n = 8)
Cohort 2 -Efavirenz+Didanosine+Tenofovir
(n = 8)
Cohort 3 -Nevirapine+Lamivudine+Tenofovir
(n = 8)
Cohort 4 -Kaletra+Stavudine+Lamivudine
(n = 5)
Subjects continued on their prescribed ARV therapy and
also received a single oral dose of UK-427,857 300 mg. Serial blood samples for
determination of UK-427,857 pharmacokinetics were collected over 12 hours post-dose.
Pharmacokinetic data (AUC12 and Cmax)
from this study was compared with that generated in a 10-day monotherapy study in HIV + ve
subjects (control).
Results:
|
Comparison
to UK-427,857 (300
mg) |
Ratio
of geometric means (%) (Cohort/Control) |
|
|
AUC12
(ng.h/ml) |
Cmax (ng/ml) |
|
|
Cohort 1 |
46.9 |
66.5 |
|
Cohort 2 |
48.3 |
76.4 |
|
Cohort 3 |
100.5 |
153.9 |
|
Cohort 4 |
264.7 |
179.6 |
Conclusions: Efavirenz-containing
regimens resulted in approximately 50% reduction in systemic exposure to
UK-427,857, while the regimen containing Kaletra resulted in an approximate
doubling in exposure. The nevirapine-containing regimen resulted in a small
increase in Cmax but no effect on AUC12.
The results of this study confirmed the results previously seen in healthy
volunteer studies and support the proposed dose adjustment recommendations for
UK-427,857.
Keywords: CCR5 antagonist; Drug Interaction; HIV positive patients
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