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Differing Darunavir Troughs With Once- and Twice-Daily Dosing in Practice
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10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Darunavir minimum concentration (Cmin) was 45% lower with once-daily dosing (for antiretroviral-naive people) than with twice-daily dosing (for experienced patients), according to an observational study of 138 patients who started darunavir/ritonavir at three French hospitals [1]. But Cmin exceeded target concentrations for almost everyone in this study. Raltegravir or nonnucleosides had little impact on darunavir Cmins in this population.
The study involved 138 people, all but 19 of them (14%) taking 600/100 mg of darunavir/ritonavir twice daily as part of a rescue regimen:
· Group 1: 57 taking 600/100 mg twice daily without raltegravir or a nonnucleoside
· Group 2: 21 taking 600/100 mg twice daily with raltegravir
· Group 3: 41 taking 600/100 mg twice daily with a nonnucleoside (with or without raltegravir)
· Group 4: 19 taking 900/100 mg once daily in their first regimen
Everyone in group 1 reached a darunavir Cmin above 550 ng/mL, the 50% effective concentration (EC50) for darunavir against protease inhibitor (PI)-resistant virus. Forty seven of these 57 people (79%) had a Cmin above 2262 ng/mL, the proposed cutoff for treatment-experienced people with 4-to-40-fold resistance to darunavir before starting this PI. Only 1 person in group 2 had a Cmin below 550 ng/mL. Ritonavir Cmin was significantly lower in group 3 than in group 1 (167 versus 294 ng/mL, P < 0.005), but that did affect darunavir Cmin:
· Group 1: 3015 ng/mL (range 819 to 6498, coefficient of variation [CV] 42.7%)
· Group 2: 2515 ng/mL (range 254 to 5418, CV 48.6%)
· Group 3: 2957 ng/mL (range 881 to 5657, CV 39.5%)
Comparing group 2 with group 1 showed that raltegravir had no significant impact on darunavir Cmin in these people. Thirteen of 21 people (62%) in group 2 had a darunavir Cmin above 2262 ng/mL, the cutoff for people with up to 40-fold resistance to darunavir.
In group 3, 20 people took etravirine, 13 efavirenz, and 8 nevirapine. Darunavir Cmin in this group did not differ from Cmin in group 1. Everyone in group 3 had a darunavir Cmin above 550 ng/mL, and 32 (78%) had a Cmin above 2262 ng/mL.
For group 4, the people starting 900/100 mg of darunavir/ritonavir in their first regimen, the investigators calculated darunavir concentrations 12 and 24 hours after dosing:
· Group 4 at 12 hours (n = 16): 3846 ng/mL (range 1013 to 14,001, CV 66.7%)
· Group 4 at 24 hours (n = 19): 1650 ng/mL (range 394 to 5367, CV 68.7%)
Everyone in this group had a darunavir Cmin above 55 ng/mL, the EC50 for darunavir against wild-type (nonmutant) virus. Three of 19 (16%) had a Cmin below 550 ng/mL, the EC50 for resistant virus. In group 4 the 24-hour concentration of 1650 ng/mL was 45.3% lower than the 12-hour Cmin in group 1, a highly significant difference (P < 0.0001) though one that should not matter for people with PI-susceptible virus. But Jean-Marie Poirier and colleagues cautioned that a lower Cmin with once-daily dosing could be clinically relevant for people starting once-daily dosing with detectable or archived PI resistance mutations..
Reference
1. Diallo M, Bonnard P, Meyohas M, et al. Darunavir and ritonavir trough plasma concentrations in routine clinical practice. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_40.
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