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Once-Daily Darunavir Troughs Stay in Active Range for All ARTEMIS Patients
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
Trough concentrations of once-daily darunavir/ritonavir stayed above the 50% effective concentration (EC50) for wild-type (nonmutant) virus in everyone taking these protease inhibitors (PIs) in the ARTEMIS trial of first-line regimens [1]. Darunavir concentrations did not correlate with side effect rates in this analysis.
The ongoing ARTEMIS study randomized untreated people to 800/100 mg of darunavir/ritonavir once daily or to 800/200 mg of lopinavir/ritonavir daily, each with tenofovir/emtricitabine. After 48 weeks 84% assigned to darunavir and 78% assigned to lopinavir had a viral load under 50 copies by a time-to-loss-of-virologic-response analysis--a result establishing the first-line noninferiority of darunavir to lopinavir [2]. Darunavir/ritonavir proved more tolerable than lopinavir/ritonavir through 48 weeks.
Almost one third of ARTEMIS participants were women, and 58% were non-Caucasian. Median pretreatment CD4 count stood at 225, and 34% of enrollees had a pretreatment viral load above 100,000 copies. The pharmacokinetic analysis focused on 335 darunavir-treated people who gave blood samples at ARTEMIS weeks 4, 8, 24, 48, 72, and 96. At weeks 4 and 24 researchers collected a trough sample immediately before darunavir dosing and another sample at least 1 hour after dosing.
Median darunavir area under the concentration-time curve (AUC, or total drug exposure in a dosing interval) stood at 87,854 ng/h/mL and ranged from 45,000 to 219,240 ng/h/mL. (Darunavir AUC averaged 61,668 ng/h/mL after 12 hours of 600/100 mg twice daily in an earlier study of 119 HIV-infected people.[3]) Median darunavir trough in ARTEMIS measured 2041 ng/mL and ranged from 368 to 7242 ng/mL. Everyone tested always had a trough above 55 ng/mL, the calculated EC50 for darunavir against nonresistant virus, corrected for protein binding. (Median trough in the earlier study of 600/100 mg twice daily was 3539 ng/mL).
Neither AUC nor trough correlated with 48-week sub-50-copy response to darunavir/ritonavir. More than 90% of patients in each of the four darunavir trough brackets had a week 48 viral load below 50 copies in an on-treatment analysis:
· Quartile 1 (< 1491.9 ng/mL): 91.1% below 50 copies (n = 79)
· Quartile 2 (1491.9 to < 2041.2 ng/mL): 96.1% below 50 copies (n = 77)
· Quartile 3 (2041.2 to < 2768.4 ng/mL): 90.4% below 50 copies (n = 73)
· Quartile 4 (>2768.4 ng/mL): 93.3% below 50 copies (n = 75)
The investigators discovered no apparent links between darunavir AUC or trough and rates of rash, nervous system or psychiatric disorders, or cardiac, gastrointestinal, liver, lipid, or glucose abnormalities.
At this point ritonavir-boosted darunavir is licensed for treatment-experienced people in a twice-daily dose of 600/100 mg. The dosage formulation used in ARTEMIS is not available.
References
1. Sekar V, Vanden Abeele C, Van Baelen B, et al. Pharmacokinetic/pharmacodynamic analyses of once-daily darunavir in the ARTEMIS study. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 769.
2. DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at week 48: ARTEMIS (TMC114-C211). 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2007. Chicago. Abstract H-718b.
3. Darunavir. aidsinfo.nih.gov. Accessed February 11, 2008.
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