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Session 97
Poster Abstracts New Antiretroviral Agents: RTIs and Pis Thursday, 1:30 - 3:30 pm Hall A |
Background: 640385 is a potent, novel protease inhibitor (PI) with low-nM in vitro IC50 against multi-PI-resistant HIV. The objectives of this study were to assess the safety, tolerability, and pharmacokinetics of 640385 following repeat administration with and without ritonavir (RTV).
Methods: A double-blind, randomized, placebo-controlled, repeat-dose, escalating study was conducted in 6 sequential cohorts of healthy subjects (n = 10/cohort, 8 active/2 placebo). Study doses, shown in the table below, were administered for 15 days. Plasma 640385 concentrations were measured by a validated LC/MS/MS assay. Descriptive statistics were used to describe model-independent pharmacokinetic parameters.
Results: Repeat administration of 640385 (±RTV) was safe and well tolerated without serious or grade 3/4 adverse events. Mild to moderate adverse events potentially related to 640385 or 640385/RTV included headache, fatigue, lightheadedness, nausea, diarrhea, abdominal discomfort, rash, and pruritis. Day-15 median (range) plasma 640385 pharmacokinetic parameters based on nominal time data are summarized by cohort in the table.
|
640385/RTV Regimen |
n |
AUC(0-t)1 (ng.h/mL) |
Cmax (ng/mL) |
tmax (hours) |
Ct (ng/mL) |
|
800 mg twice daily |
6 |
221 (74, 402) |
54 (15, 113) |
3.8 (1.5, 5.0) |
3.1 (1.1, 5.6) |
|
100/100 mg once daily |
8 |
1939 (1119, 2478) |
247 (175, 302) |
3.8 (2.5, 5.0) |
17 (6.3, 45) |
|
250/100 mg once daily |
6 |
2489 (1772, 4486) |
398 (291, 609) |
4.0 (2.5, 4.0) |
18 (9.6, 32) |
|
50/100 mg twice daily |
8 |
1175 (620, 1985) |
154 (100, 249) |
4.5 (3.0, 6.0) |
61 (27, 120) |
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150/100 mg twice daily |
8 |
2145 (763, 3049) |
346 (141, 420) |
4.5 (3.5, 5.0) |
104 (36, 217) |
|
300/100 mg twice daily |
8 |
2735 (2244, 7329) |
463 (366, 998) |
4.0 (2.5, 6.0) |
132 (83, 387) |
t=12h for BID regimens and 24h for QD regimens
Conclusions: Repeat administration of 640385 (± RTV) was safe and well-tolerated. All 640385/RTV twice-daily regimens achieved median day-15 640385 Ct above 28 ng/mL, the estimated clinical target based on in vitro IC50 for PI-resistant virus adjusted for protein binding. 640385 will be further evaluated in studies in PI-experienced HIV-infected subjects.
Keywords: 640385; protease inhibitor; pharmacokinetics
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