585
Beneficial Pharmacokinetic Interaction between Atazanavir and Lopinavir/Ritonavir
Paul Pham*1, T Parsons1, C Flexner1, L Vasist3, E Redpath1, E fuchs1, K Carson1, S Agarwala2, and P Barditch-Crovo1
1Johns Hopkins Univ, Baltimore, MD, US; 2Bristol-Myers Squibb, Plainsboro, NJ, US; and 3Univ of North Carolina at Chapel Hill, US
Background: The combination of lopinavir/ritonavir (LPV/r) and
atazanavir (ATV) with nucleoside reverse transcriptase inhibitors (NRTI) may be
used as a salvage regimen. Since these agents, to various degrees, are
substrates, inducers, and inhibitors of CYP450 3A4, there is concern for
alterations in the pharmacokinetics of these combined agents. We conducted a pharmacokinetic
study to determine the interactions among ATV, RTV, and LPV.
Methods: HIV-negative subjects (n = 15) received a combination of ATV, RTV, and LPV in the
following sequence:
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Period I
(days 1-10)
ATV/r 300/100 mg once
daily
|
Period II
(days 11-24)
ATV 300 mg once
daily +
LPV/r 400/100 mg twice
daily
|
Period III
(days 25-34)
ATV/r 300/100 mg once
daily +
LPV/r 400/100 mg twice
daily
|
Intensive pharmacokinetic
analysis was performed on days 10, 24, and 34. Paired t-test was used for pair-wise comparison of log transformed pharmacokinetic
parameters of ATV and LPV.
Results: In period II (ATV 300 mg every morning + LPV/r 400/100
mg twice daily), ATV Cmin geometric mean (GM) was higher compared to
period I (ATV/r 300/100 mg every morning) (GM 0.75 vs 0.51 mg/mL; GM ratio [GMR] 1.45, 90%CI 1.19 to 1.77, p = 0.006). However, ATV AUC0-24
(GM 36.40 vs 39.62 mg·hr/mL; GMR 0.92, 90%CI 0.80 to 1.05, p = 0.28) and ATV Cmax (GM 3.49 vs 4.23 mg/mL; GMR 0.83 (0.70 to 0.97, p = 0.06) did not differ. The addition of RTV 100 mg in period III
(ATV 300 mg every morning + RTV 100 mg every morning + LPV/r 400/100 mg twice
daily) did not significantly increase ATV Cmin (GM 0.84 vs 0.75 mg/mL; GMR 1.13, 90%CI 0.91 to 1.40, p = 0.34) or ATV AUC0-24 (GM 39.59
vs 36.40 mg·hr/mL; GMR 1.09, 90%CI
0.99 to 1.20, p = 0.14) compared with
period II. However, the additional RTV in period III resulted in a higher LPV Cmin
(GM 5.12 vs 3.99·mg/mL; GMR 1.28, 90%CI 1.15 to 1.43, p
= 0013) but LPV AUC0-12 and Cmax were not significantly
different. LPV pharmacokinetic parameters in period II were comparable to
historical control subjects receiving LPV/r 400/100 mg twice daily. All studied
regimens were well tolerated. Indirect hyperbilirubinemia was the only grade 3
and 4 adverse events reported, with 3 grade 3 elevations and 1 grade 4 elevation
reported in period I and 1 grade 4 elevation reported in period III.
Conclusions: The combination of ATV 300 mg once daily + LPV/r
400/100 mg twice daily resulted in a favorable pharmacokinetic profile for both
ATV and LPV and could be further evaluated in treatment-experienced patients requiring
a dual-boosted PI-containing regimen.
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