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Early Look at Once-Daily Darunavir/Ritonavir for Treatment-Experienced Patients
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10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Darunavir/ritonavir taken once daily at a dose of 900/100 mg worked well in a nonrandomized study of 25 people with some antiretroviral experience, including one or more previous protease inhibitors (PIs) [1]. No one in this study had darunavir-related mutations before starting darunavir/ritonavir. Once-daily 800/100-mg darunavir/ritonavir is licensed for treatment-naive patients, but the sanctioned dose for experienced people remains 600/100 mg twice daily.
The study by Barcelona clinicians involved 25 people, 12 of them with a viral load under 50 copies. Among people with a detectable load, the median load was 20,000 copies/mL. Median CD4 count stood at 330 and median body mass index at 24 kg/m(2). Thirteen people had HCV infection. The study group had a median of 2 nucleoside-related mutations and 2 nonnucleoside mutations, but a median of 0 PI mutations (range 0-2) meaning some people had a few PI mutations. No one had a darunavir-specific mutation. People had taken a median of 5 earlier regimens, including 2 PI regimens, and a median of 1 PI regimen had failed.
All study participants began 900/100 mg of darunavir/ritonavir once daily with at least one other drug judged to be active against their virus. (Four people took raltegravir.) After 6 months, everyone had an undetectable viral load and the median CD4 count rose by 67. Liver function and lipid profiles did not change significantly. No one had a serious side effect, and no one stopped treatment.
A darunavir minimum concentration (Cmin) above 0.055 microgram/mL is judged sufficient to control nonmutant virus. With a group median Cmin of 1.83 microgram/mL after at least 2 weeks of treatment, no one had a dangerous sub-0.055 level. Only 1 person had a darunavir Cmin below 0.550 microgram/mL, judged to be the concentration needed to control virus with 10-fold resistance to darunavir. Other median (and interquartile range) darunavir values were:
⋅ Maximum concentration: 8.19 micrograms/mL (7.19 to 9.97)
⋅ Time to maximum concentration: 2 hours (1 to 3.5)
⋅ 24-hour area under the curve: 9.13 micrograms/hour/mL (72.9 to 122.6)
⋅ Clearance: 9.86 L/hours (7.37 to 12.35)
Darunavir concentrations did not differ significantly between men and women or between people with and without HCV. Nor did the investigators see any significant darunavir interactions with benzodiazepines (in 6 people), raltegravir (in 4), methadone (in 3), statins (in 3), methadone (in 3), or proton pump inhibitors (in 3). But they cautioned that these numbers are too small to support any firm conclusions about interactions.
In a workshop study reported separately by NATAP, 600 mg of efavirenz added to this same once-daily darunavir/ritonavir dose significantly cut darunavir concentrations in healthy volunteers [2]. But again the darunavir Cmin always remained above 0.055 microgram/mL.
References
1. Curran A, Gutierrez M, Lopez R, et al. Pharmacokinetics, efficacy and safety of darunavir/ritonavir 900/100 mg once-daily. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_14.
2. Lee LS, Soon GH, Shen P, Flexner C, Pham P. Pharmacokinetics of darunavir 900mg and ritonavir 100 mg (DRV/rtv) once daily when co-administered with efavirenz 600mg once daily in healthy adult volunteers. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_29.
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