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Darunavir Levels Not Affected by Gender, Race, or Age in GRACE Trial
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
GRACE, a trial of darunavir/ritonavir in a largely female and ethnically diverse group of antiretroviral-experienced people, found that darunavir concentrations did not differ substantially by gender, race, age, weight, hepatitis B coinfection, or cotreatment with tenofovir or the nonnucleoside etravirine [1].
This US-Canadian-Puerto Rican trial enrolled 429 adults, including 287 women (67%), 264 blacks (62%), 96 Hispanics (22%), and 55 whites (15%) [2]. Everyone had a viral load above 1000 copies and had taken a protease inhibitor or nonnucleoside regimen for at least 12 weeks. No one had tried darunavir, etravirine, tenofovir, or enfuvirtide. All enrollees started 600/100 mg of darunavir/ritonavir twice daily with an optimized background regimen that could include etravirine. Median age stood at 43 in women and 45 in men, median CD4 count at 210 in women and 175 in men, and average viral load at about 45,000 copies in women and 55,000 copies in men.
GRACE investigators measured darunavir concentrations in everyone at study weeks 4, 8, 24, and 48. A subgroup had intensive sampling for darunavir-level analyses at weeks 4, 24, and 48. This study focused on 376 people (66% women, 61% black, 22% Hispanic) who had sparse sampling at weeks 4, 8, 24, and 48, and on 37 people (68% women, 68% black, 27% Hispanic) who had intensive sampling.
In the sparse-sampling group, median darunavir area under the curve (AUC) measured 60,642 ng/h/mL (range 26,117 to 128,790), while median trough concentration stood at 3642 ng/mL (range 931 to 9570). Everyone tested had a trough concentration above the protein binding-corrected median effective concentration (EC50) for darunavir-resistant virus (550 ng/mL). The overall median trough was 6.5 times higher than the EC50 for resistant virus. Values in the intensively sampled group reflected those in the larger sparse-sampling group.
Median darunavir AUC over 12 hours did not vary between women and men (61,190 and 59,702 ng x h/mL) or between blacks, Hispanics, and whites (60,451, 58,215, and 63,705 ng x h/mL). Trough concentrations were also equivalent in women and men (3663 and 3566 ng/mL) and in blacks, Hispanics, and whites (3588, 3576, and 3721 ng/mL).
The investigators also reported 12-hour AUC and trough concentration in numerous subgroups of the trial population (in parenthesis below are numbers of patients)
· Taking etravirine (189) or not (187)
· Taking tenofovir (318) or not (58)
· With HBV (14) or without (362)
· Age 30 or under (39), 30 to 49 (260), 50 to 64 (68), and 65 or over (9)
· Weight at study entry at or under 62.33 kg (94), 62.34 to 73.93 g (96), 73.94 to 87.09 kg (92), and over 87.09 kg (94)
None of these comparisons disclosed any clinically meaningful differences in darunavir AUC or predose concentration. Nor did GRACE reveal any gender- or race-based differences in tolerance of darunavir/ritonavir.
References
1. Kakuda T, Sekar VJ, Vis P, et al. Intrinsic/extrinsic covariates and darunavir pharmacokinetics in treatment-experienced patients in GRACE (Gender, Race And Clinical Experience). 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 16.
2. Squires K, Currier J, Bridge D, et al. GRACE (Gender, Race And Clinical Experience): 48-week results of darunavir/r-based therapy in the largest trial in North America focused on treatment-experienced women. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200722319
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