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Session 86 Poster Abstracts
Pharmacology of Protease Inhibitors
Tuesday, 1:30 - 3:30 pm
Poster Hall


616    
Pharmacokinetics of Reduced-dosed Indinavir/Ritonavir 400/100 mg every 12 hours in HIV-1-infected Thai Patients
M Boyd*1,2, D Burger3, P Mootsikapun4, T Chuenyam1, S Ubolyam1, J Sangkote1, P Bunyaprawit4, M Horsakulchai4, J Lange1,5, D Cooper1,2, P Phanupak1,6, and K Ruxrungtham1,6
1The HIV Netherlands Australia Thailand Res. Collaboration (HIVNAT), Thai Red Cross AIDS Res. Ctr. Bangkok, Thailand; 2Natl. Ctr. in HIV Epidemiology and Clin. Res., Univ. of New South Wales, Sydney, Australia; 3Univ. Med. Ctr. Nijmegen, The Netherlands; 4Srinagarind Hosp., Faculty of Med., Khon Kaen Univ., Thailand; 5Acad. Med. Ctr., Amsterdam, The Netherlands; and 6Chulalongkorn Univ. Faculty of Med., Bangkok, Thailand

Background:  We have previously demonstrated that a regimen containing indinovir (IDV)/ritonavir (RTV) 800/100 mg every 12 hours was as effective as unboosted IDV 800 mg every 8 hours in Thai HIV-1-infected patients, but the former regimen was also associated with more IDV-related toxicity. Based on this experience, and on preliminary data of reduced-dose IDV/RTV 400/100 mg every 12 hours in Caucasian patients, a trial of this reduced dose IDV/RTV was initiated at Srinagarind Hospital, Khon Kaen, Thailand.

Methods:  For this pharmacokinetic substudy, 19 patients (8 females) were randomly selected. All patients were using IDV/RTV (400/100 mg every 12 hours) + 2 NRTI for at least 24 weeks. A 12-hour pharmacokinetic curve was recorded after an overnight fast. Plasma levels of IDV and RTV were determined by a validated HPLC method. Pharmacokinetic parameters were calculated by noncompartmental methods. Virological failure was defined according to the most recent DHHS guidelines as a viral load above 400 copies/mL at week 24.

Results:  Median baseline values for CD4 and viral load were 13 cells/mm3 and 167,000 copies/mL, respectively. The median and interquartile ranges (IQR) for IDV AUC, Cmax and Cmin were 18.1 (15.3 to 23.8) mg/L.h, 4.1 (3.6 to 4.8) mg/L, and 0.17 (0.12 to 0.30) mg/L, respectively. These values represent 37%, 39%, and 24% of the AUC, Cmax and Cmin values as found respectively for the IDV/RTV 800/100 dose in HIV-1-infected Thai patients; this indicates a nonlinear decrease in IDV exposure with a 50% lower dose. Median (+IQR) RTV AUC, Cmax and Cmin were 10.4 (5.9-13.5) mg/L.h, 1.9 (1.5 to 3.2) mg/L, and 0.18 (0.13-0.27) mg/L, respectively, and these values reflect approximately 25% lower exposure to RTV despite the same RTV dose in the 800/100 mg regimen. A non-significant trend (p = 0.18, Mann-Whitney test) was observed for higher exposure to IDV in female vs male patients. There were 3 subjects with an IDV Cmin below the target value of 0.10 mg/L, of whom 1 had virological failure (33%). Among the other 16 subjects with an IDV Cmin above 0.10 mg/L there was also 1 virological failure (6%). This difference was not statistically significant (p = 0.30, Fischer exact Test).

Keywords: indinavir; pharmacology; developing countries