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Pharmacokinetics and Pharmacodynamics of a Double-boosted PI Regimen of Saquinavir and Lopinavir/Ritonavir in Treatment-naive HIV-1-infected Adults
Jasper van der Lugt*1,2, Jasper van der Lugt*1,2, S Autar1,2, S Autar1,2, S Ubolyam1, D Cooper1,3, D Cooper1,3, J Lange1,2,4, J Lange1,2,4, J Lange1,2,4, P Phanuphak1,5, P Phanuphak1,5, D Burger6, E Fernandez Garcia2, F Wit2,4, F Wit2,4, K Ruxrungtham1,5, and K Ruxrungtham1,5
1HIV Netherlands Australia Thailand (HIV-NAT) Res Collaboration, Thai Red Cross AIDS Res Ctr, Bangkok; 2Intl Antiviral Therapy Evaluation Ctr, Amsterdam, The Netherlands; 3Natl Ctr for HIV Epidemiology and Clin Res, Univ of New South Wales, Australia; 4Academic Med Ctr, Univ of Amsterdam, The Netherlands; 5Faculty of Med, Chulalongkorn Univ, Bangkok, Thailand; and 6Radboud Univ Med Ctr, Nijmegen, The Netherlands
Background: The combination of lopinavir/ritonavir (LPV/r)
plus saquinavir (SQV) has been investigated mainly as salvage therapy in
heavily treatment-experienced patients. Limited data are available about the
optimal dosing of this combination in Thai patients. We performed a
dose-finding study in treatment-naive Thai patients to describe the
pharmacokinetics and pharmacodynamics in this
population.
Methods: We randomized 48 treatment-naive patients to
either LPV/r 400/100 mg + SQV 1000 mg twice daily (group A), LPV/r 400/100 mg +
SQV 600 mg twice daily (group B), LPV/r 266/66 mg + SQV 1000 mg twice
daily (group C), or LPV/r 266/66 mg + SQV 600 mg twice daily (group D) in this
24-week, prospective study. We carried out 12-hour pharmacokinetic analysis 2 weeks
after start of treatment. Plasma pharmacokinetic parameters (AUC, Cmax, Cmin)
were calculated using noncompartmental methods. An
ANOVA 4-arms model with a 95%CI was used to detect any significant differences
among the groups. The dynamics of viral decline were determined using a
non-linear least square fitting model for the first phase and a linear splines model for the second phase.
Results: Of the total, 5 patients discontinued study
medication (4 for personal reasons and 1 because of grade IV liver enzyme
elevations); 1 was excluded from analysis because of nonadherence.
Mean (SD) values for LPV AUC (mg/L.h), Cmax (mg/L) and Cmin
(mg/L) were 129.03 (14.88); 14.91 (1.30); 6.53 (1.11); 121 (18.19); 121.34 (18.19);
6.40 (1.17); 13.30 (1.92); 62.96 (9.96); 8.02 (1.10); 2.93 (0.59); 73.28 (6.59);
9.10 (0.74); 3.13 (0.58) for groups A through D, respectively. For SQV the mean
(SD) values were 35.34 (6.34); 5.30 (0.81); 1.25 (0.28); 26.18 (6.24); 3.42 (0.71);
0.89 (0.26); 25.98 (6.06); 3.96 (0.81); 0.89 (0.20); 15.53 (2.96); 2.31 (0.42);
0.52 (0.12) for groups A through D, respectively. Subtherapeutic
Cmin values were observed in 4 patients (1
in every group, all for LPV). There were no significant differences in first
and second phase of viral decline (p
= 0.92 and 0.27, respectively) between arms. The overall mean of phase I
half-life (SD) was 5.67 (0.05) days. The proportion of patients having a viral
load <50 copies/mL at week 24 was 38.5% for A,
77.7% for B, 60.0% for C, and 61.5 % for D (intention to treat). The
proportions <400 copies were 61.5%, 77.7%, 80.0%, and 76.9% for A through D,
respectively.
Conclusions: The pharmacokinetics parameters for all groups
were adequate, and no significant difference in the rate of plasma HIV-1 RNA
decline was found. However, overall rate of viral decline was slower than
expected.
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