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Session 63 Poster Session Drug-Drug Interactions Session Time: 4:30-6:30 pm Room 4E-F

440-W. Pharmacokinetic Interaction between Lopinavir/r and Amprenavir in Salvage Therapy C. Solas*1, A. M. Quinson2, C. Couprie1, I. Ravaux2, I. Poizot-Martin3, A. Durand1, and B. Lacarelle1 1Timone Hosp., 2Conception Hosp., and 3Sainte-Marguerite Hosp., Marseille, France Background: Lopinavir/r (LPV/r) plus amprenavir (APV) in multiexperienced patients is of growing interest that needs to be validated in terms of pharmacokinetic profile, safety, and efficacy. Ritonavir (RTV) present in LPV/r is a potent inhibitor of CYP3A4 and both LPV and APV are substrates of the CYP3A4. Multiple drug-drug interactions, including several protease inhibitors, which are substrate and/or inhibitor and/or inductor of CYP3A4, could not always be predicted because of the multiple molecular mechanisms involved. Methods: Plasma trough concentrations (Cmin) of APV and LPV from 46 HIV-infected patients were determined by HPLC. APV/LPV/r combinations were assessed at 600/400/100 mg BID (n=9) and 750/400/100 mg BID (n=13) and compare with the standard combination APV/RTV at 600/100 mg BID (n=21) and 750/100 mg BID (n=3). Plasma samples were drawn 10-12 hours post ingestion. Statistical comparison was performed using the non-parametric Mann-Whitney test. Results: 51 and 24 plasma samples of APV Cmin and LPV Cmin were analyzed. At 600 mg BID, median APV Cmin (range, CV) was statistically lower when associated with LPV/r: 859 ng/mL (573-2069, 49%) compared to 1772 ng/mL (783-6746, 59%) when associated with RTV (p=0.004). At 750 mg BID, no statistical difference was reported between the median APV Cmin associated with LPV/r or RTV (p=0.215): 1108 ng/mL (761-4034, 63%) vs 1655 ng/mL (1341-1783, 12%). Median LPV Cmin were 5286 ng/mL (1034-12,444, 64%) and 4429 ng/mL (1515-8016, 45%) with APV 600 and 750 mg BID, respectively. These results were concordant with the median LPV Cmin usually observed when given alone 5239 ng/mL (436-14,092, 53%) (historical data, n=94 patients). Conclusions: Pharmacokinetic of LPV/r plus APV showed a 51% and 33% decreased of the median APV Cmin for 600 and 750 mg BID compared to patients treated by the association APV/RTV 600/100 or 750/100 mg BID. However, 85% of the patients taking APV/LPV/r had a median APV Cmin up to 3-fold the Cmin usually observed with the standard 1200-mg BID regimen. In contrast, median LPV Cmin was not affected by the association with APV whatever the dose. Therapeutic drug monitoring is available and useful in such association to evidence any decreased or increased concentrations leading to adverse events or virologic failure. Further studies are required to evaluate the efficacy and the tolerance of this regimen.

©2002 9th Conference on Retroviruses and Opportunistic Infections