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Pharmacodynamics (PD) of Indinavir (IDV) in Protease-Naive HIV-Infected Patients Receiving ZDV and 3TC E. P. ACOSTA*1, D. V. HAVLIR2, D. D. RICHMAN2, X. J. ZHOU1, M. HIRSCH3, A. C. COLLIER4, P. TEBAS5, and J.-P. SOMMADOSSI1 for the ACTG 343 TEAM. 1Univ. of Alabama at Birmingham; 2Univ. of California at San Diego; 3Boston, MA; 4Univ. of Washington; and 5Washington Univ Background: Systemic drug exposure is critical in achieving and maintaining plasma HIV RNA suppression. We evaluated pharmacologic determinants of viral suppression in a cohort of patients treated with IDV, ZDV, and 3TC in ACTG 343.
Methods: Subjects received open-label triple therapy for 6 months. IDV troughs were obtained between 6-10h (wks 4, 8, 20); peak levels were collected 0.5-1.0h post-dose (wk 24). Plasma HIV RNA was collected at baseline and every 4 wks. Efficacy variables for exploratory PD included: nadir, decay slope, % change, log decline, and normalized area-under-the-curve (NAUC). Subjects with IDV peak/troughs and/or multiple steady-state levels were analyzed using a one-compartment, linear elimination model with Bayesian estimation. Pharmacokinetic (PK) parameters were compared between subjects with or without virologic suppression (<200 copies/ml at wk 24). Subjects were also assigned as responders (1) or non-responders (0) according to whether plasma HIV RNA was > or < 1.5 log10 drop at wk 4, respectively. Troughs and corresponding 0 or 1 were divided into equal groups; mean troughs and fraction response for each group were plotted.
Results: A total of 174/509 patients entered the PK substudy. For PK/PD analyses, 208 concentration-time points remained for 90 patients. Modeled IDV troughs (median; 229 vs 137 ng/ml) were significantly different between those with < 200 (n=71) and > 200 copies/ml (n=19) at 24 wks (P³0.006). A significant relationship was observed (r=0.34, P<0.05) between measured IDV troughs at wk 4 (n=36) and log change in plasma HIV RNA at wk 4 (Emax³1.9, EC50³25.3ng/ml). Fraction response was also related to IDV troughs (r=0.8, P<0.01) using an Emax model (Emax³97%, EC50³37ng/ml). The 90% response rate corresponded to an IDV trough of 110ng/ml.
Conclusions: IDV PK parameters showed a significant difference in C8H between patients with < or >/= 200 copies/ml plasma HIV RNA at wk 24. IDV trough levels were significantly related to changes in plasma HIV RNA using Emax models. These data suggest the minimum effective IDV trough concentration for naive patients receiving concomitant ZDV and 3TC is 110 ng/ml.
Key Words: Indinavir, Pharmacodynamics, Pharmacokinetics
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© 7th
Conference on Retroviruses and Opportunistic Infections, |