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Background: HMG-CoA reductase inhibitors such as ATO and PRA may be used with the HIV-protease inhibitor ABT-378/r to treat hyperlipidemia. ATO appears to be more dependent on CYP3A for clearance than PRA; neither inhibit nor induce CYP3A in vivo. ABT-378/r is metabolized by and inhibits CYP3A; ritonavir potently inhibits ABT-378 metabolism.

Methods: Healthy adult male and female volunteers (n=12/drug) completed 4 days of ATO or PRA (20 mg QD) in the presence and absence of ABT-378/r (400/100 mg BID for 14 days). Pharmacokinetic (PK) assessments were obtained over the dosing interval for each parent drug, o-OH- and p-OH-ATO, PRA metabolite SQ-31,906, and HMG-CoA reductase inhibitory activity (RIA). ATO and PRA were administered 30 minutes prior to breakfast; ABT-378/r 30 minutes after breakfast and dinner. PK parameters were calculated by noncompartmental methods.

Results: ABT-378/r increased ATO Cmax and AUC central values by 4.7 and 5.9-fold, respectively; increased RIA Cmax and AUC by 4.5 and 2.5-fold, respectively; substantially reduced o-OH-ATO Cmax and AUC; and substantially increased p-OH-ATO Cmax and AUC (p<0.02 for all comparisons). ABT-378/r increased PRA, SQ-31,906 and RIA Cmax and AUC by about 30%; only the change in RIA AUC was statistically significant (p=0.03). ATO or PRA had no clinically or statistically significant effect on ABT-378 or ritonavir PK.

Conclusions: During administration of ATO with ABT-378/r, careful monitoring for adverse events and laboratory abnormalities is warranted at all ATO dose levels, particularly >10 mg/day; an alternative agent should be considered. No adjustment of PRA dose is recommended when co-administered with ABT-378/r. No dosage adjustment of ABT-378/r is recommended during co-administration with ATO or PRA.

Abbott Laboratories, Abbott Park, Illinois

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