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Background: ABT-378 is a potent HIV protease inhibitor that has shown excellent antiviral activity. ABT-378 metabolism is uniquely inhibited by ritonavir (rtv), resulting in large increases in exposure with minimal doses of rtv. ABT-378/r has been coformulated at a 4:1 ratio; 400/100mg BID has been selected for registrational clinical trials. The multiple-dose PK of ABT-378/r BID regimens in HIV+ subjects were evaluated for 24 weeks(wk).
Methods: Antiretriviral naïve subjects were assigned ABT-378/r 200/100, 400/100 or 400/200mg BID with stavudine and lamivudine. Antiretroviral experienced subjects received ABT-378/r 400/100 or 400/200mg BID with nevirapine and nucleosides. Doses were taken without regard to food. ABT-378 and rtv 12-h dosing interval plasma levels were measured by HPLC in 58 subjects over 24 wk. Ex vivo ABT-378 protein binding (PB) were determined by ultrafiltration (n=8).
Results: ABT-378 and rtv AUC, Cmax and Cmin did not differ over wk 3 to 24 (p>0.05). Overall, ABT-378 and rtv AUC were highly correlated (R>0.5). Mean steady-state(ss) ABT-379 AUC for the chosen clinical dose of 400/100mg ABT-378/r was 34% higher than 200/100mg (p=0.05); ABT-378 AUC for 400/200mg was 54% higher than 400/100mg (p<0.05). Rtv AUC for 400/200mg was 3-fold higher than 400/100mg (p<0.05). Mean ss ABT-378 Cmin for 400/100mg BID was >30-fold above the PB-adjusted IC50 for wild-type HIV-1. ABT-378 PB ranged from 98 to 99% at therapeutic concentrations.
Conclusions: In HIV+ subjects dosed for 24 wk, ABT-378/r at the selected dose for registration clinical trials, 400/100mg BID, provides mean ABT-378 exposures at least 30-fold above the PB-adjusted IC50 for wild-type virus.
Abstract prepared by Abbott Laboratories
From the 39th ICAAC
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New/Newsworthy
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Multiple–Dose Pharmacokinetics of
ABT-378/Ritonavir(ABT-378/r) in HIV+ Subjects |
