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13th International AIDS ConferenceDurban, South Africa - July 9-July 14, 2000 |
Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrB546)
Hsu A, Williams L, Chiu Y-L, Hill L, McMillan F, Lamm J, Rynkiewicz K, Foit C, Ji Q, Hutman W, Ryan J, Sun E, Japour A;;; A. Hsu, Abbott Laboratories, D4PK, AP13A, 100 Abbott Park Rd, Abbott Park, IL, United States, Tel.: +1 847 937 2961, Fax: +1 847 938 5193, E-mail: ann.hsu@abbott.com
BACKGROUND: Ritonavir significantly improved pharmacokinetic profiles of protease inhibitors indinavir, saquinavir, and nelfinavir, alleviating food effects and allowing reduced doses and less frequent dosing in dual protease inhibitor regimens. This study assesses PK interaction between RTV and APV.
METHODS: Three RTV-APV regimens (N = 12/Grp) (I) 400R+450A, (II) 400R+750A, and (III) 200R+1200A were assessed under nonfasting conditions. All subjects received one 1200 mg APV alone on Day 1, and their respective RTV bid doses starting Day 2. APV+RTV combination was to be co-dosed for 5 days starting on Day 12.
RESULTS: Due to high incidences of rash starting Day 4, only one dose of APV was given with RTV on Day 12. Seventeen subjects finished the 12-day study. Median APV AUC for Grps I, II, and III were 46, 39, and 76 mcgx h/mL, C12h were 0.57, 0.63, and 1.74 mcg/mL, and Cmax were 1.4, 2.2, and 5.0 mcg/mL, respectively, as compared to steady-state (ss) APV AUCt of 18.5 mcgx h/mL, Cmax 5.4, and C12h of 0.28 mcg/mL at clinical dose. APV AUC, Cmax, and C12h are not stat. significantly different between Grps. I and II. Although Grp. III had significantly higher mean APV exposure than those of Grps. I and II, its elimination half-life was 50% shorter. Relative to APV 1200 mg BID, all three combo bid regimens would yield higher ss APV C12h and AUC values. APV appeared to have no effect on RTV PK. Median RTV C12h values were 2.1, 2.9, and 0.62 mcg/mL for Grp. I, II, and III, respectively. RTV and APV IC50 in 50% human serum are é ºim0.9 and 0.3 mcg/mL, respectively.
CONCLUSIONS: RTV improves the PK profile of APV. All three regimens would yield APV C12h that exceeds the protein-binding adjusted IC50. Regimens I and II would also yield RTV C12h that exceed IC50. A high incidence of rash was observed following APV dosing. Clinical evaluation of these regimens is needed to assess antiviral activity and safety.
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