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Lopinavir/Ritonavir 500/125 mg Twice-daily + Efavirenz Approximate the Pharmacokinetic Exposure of LPV/r 400/100 mg Twice-daily Administered Alone in Healthy Adult Subjects
Juki Ng*, C Klein, J Xiong, Y L Chiu, T Doan, C Rolle, C Holas, R Stryker, and B Bernstein
Abbott Labs, Abbott Park, IL, US
Background: Co-administration of lopinavir/ritonavir
(LPV/r) 200/50-mg tablets at a dose of 400/100 mg or 600/150 mg twice-daily
with efavirenz (EFV) 600 mg results in 13 to 20% lower or 36% higher LPV
exposure, respectively, compared to LPV/r 400/100 mg twice-daily administered
without EFV. A new LPV/r 100/25-mg tablet has recently been developed making
possible a dose of LPV/r 500/125 mg. This study compared the LPV/r
pharmacokinetic parameters of 500/125 mg twice-daily with EFV vs 400/100-mg twice-daily
alone.
Methods: For 10 days, 19 healthy HIV-negative adult
subjects received LPV/r tablet 400/100 mg twice-daily (nonfasting) followed by
LPV/r tablet 500/125 mg twice-daily (nonfasting) + 600 mg EFV every hour of
sleep (QHS) (fasting) for 10 days. Serial blood samples were collected over the
dosing interval for LPV/r concentrations on days 10 and 20. Pharmacokinetic
parameters were compared using 90% confidence intervals. Safety and
tolerability were assessed throughout the study.
Results: LPV/r 500/125 mg twice-daily
co-administered with EFV produced similar average LPV exposure compared to
LPV/r 400/100 mg twice-daily dosed alone. Ritonavir exposure was modestly
increased in subjects receiving LPV/r 500/125 mg. LPV exposure dosed 500/125 mg
twice-daily most closely approximated exposure of LPV/r dosed alone. Adverse
events were similar to those previously described for LPV/r and EFV. The
majority of adverse events noted to be mild in severity. Pharmacokinetic
parameters are shown in the table.
|
Test vs Reference
|
Pharmacokinetic Parameter
|
|
Relative Bioavailability
|
|
Central Values*
|
Point
Estimate
(T/R)
|
90% Confidence
Interval
|
|
Test (T)
|
Reference (R)
|
|
|
Lopinavir
|
|
LPV/r + EFV vs
LPV/r alone
|
Tmax (h)
|
4.32
|
4.21
|
--
|
--
|
|
Cmax (μg/mL)
|
13.49
|
12.04
|
1.121
|
1.023 to 1.228
|
|
AUC12 (μg*h/mL)
|
113.16
|
106.80
|
1.060
|
0.956 to 1.174
|
|
C0 (μg/mL)
|
6.46
|
6.77
|
0.954
|
0.822 to 1.108
|
|
Cmin (μg/mL)
|
4.97
|
5.52
|
0.902
|
0.784 to 1.037
|
|
|
Ritonavir
|
|
LPV/r + EFV vs
LPV/r alone
|
Tmax (h)
|
4.11
|
4.00
|
--
|
--
|
|
Cmax (μg/mL)
|
1.28
|
1.01
|
1.261
|
1.057 to 1.504
|
|
AUC12 (μg*h/mL)
|
6.84
|
5.71
|
1.199
|
1.050 to 1.369
|
|
C0 (μg/mL)
|
0.25
|
0.23
|
1.113
|
0.910 to 1.361
|
|
Cmin (μg/mL)
|
0.16
|
0.15
|
1.103
|
0.924 to 1.315
|
|
|
|
|
|
|
|
* Geometric mean for Cmax, AUC12, C0
and Cmin; Arithmetic mean for Tmax.
|
Central Values
|
LPV/r BID + EFV every hour of sleep
|
|
400/100 mg
N = 17
|
500/125 mg
N = 19
|
600/150 mg
N = 23
|
|
Cmax (µg/mL)
|
0.869
|
1.121
|
1.356
|
|
Cmin (µg/mL)
|
0.585
|
0.902
|
1.320
|
|
C0 (µg/mL)
|
0.732
|
0.954
|
1.362
|
|
AUC12 (µg·h/mL)
|
0.796
|
1.060
|
1.357
|
Conclusions: LPV/r at a dose of 500/125 mg twice-daily
co-administered with EFV approximates the pharmacokinetic exposure of LPV/r
400/100 mg twice-daily when administered alone. The regimens were well
tolerated.
|
