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Background: ABT-378/r is an HIV-protease inhibitor (PI) with high antiretroviral activity in Phase II/III trials. At the ABT-378/r clinical dose of 400/100 mg BID, ABT-378 mean pre-am Ctrough exceeds wt-HIV EC50 by >75-fold. EFV, an NNRTI, may be combined with ABT-378/r in HAART. Both are metabolized by and inducers of CYP3A.

Methods: Healthy volunteers completed 9 days of ABT-378/r 400/100 mg BID (n=7), EFV 600 mg QHS (n=12), or combination (n=11); 24 h pharmacokinetic (PK) assessments were obtained for each drug. PI-experienced HIV+ subjects had 12 h PK after 2 weeks ABT-378/r 400/100 mg BID + EFV 600 mg QHS, followed by either ABT-378/r 400/100 mg (n=24) or 533/133 mg (n=26) BID + EFV for additional 3 weeks with background NRTI. ABT-378/r doses were administered with food. PK parameters were calculated by noncompartmental methods.

Results: In healthy volunteers, EFV Cmax, AUC and Cmin were reduced by < 16% during ABT-378/r (p>0.35). Ritonavir pharmacokinetic parameters were unchanged (p>0.52). ABT-378 Cmax was unaffected (p=0.84), but AUC and Cmin were 19% (p=0.14) and 39% (p=0.08) lower, respectively. In HIV+ subjects, ABT-378 AUC and Cmin were reduced by 25 and 44%, respectively, during EFV + ABT-378/r 400/100 mg BID, compared to historical controls. ABT-378/r 533/133 mg BID + EFV produced mean ABT-378 AUC and Cmin 45 and 88% higher than 400/100 mg BID + EFV, respectively.

Conclusions: No dosage adjustment of EFV is necessary when co-administered with ABT-378/r. At 400/100 mg BID, AUC and Cmin of ABT-378 were reduced by » 20-25 and 40-45%, respectively, in healthy volunteers and HIV+ subjects. Increasing ABT-378/r by 33% to 533/133 mg (4 x 133/33 mg capsules) BID during EFV co-administration produced concentrations similar to those achieved with 400/100 mg BID alone.

Abbott Laboratories, Abbott Park, IL

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