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Etravirine Levels Higher When Added After Darunavir vs With Darunavir
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10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Etravirine trough concentrations were significantly higher when patients already taking darunavir/ritonavir added etravirine than when they started the drugs together [1]. Whether this difference will hold true for most people starting these two antiretrovirals sequentially is difficult to say because of the small size of this comparison.
Chiara Tommasi and coworkers at Rome's National Institute for Infectious Diseases L. Spallanzani studied people taking a failing regimen who switched to a combination including raltegravir (400 mg twice daily) with or without darunavir/ritonavir (600/100 mg twice daily). Some people also started etravirine (200 mg twice daily). The investigators measured trough concentrations of the three antiretrovirals on treatment days 14 and 30 and averaged those readings. Several regimens had failed in these study participants, and they had virus resistant to most other antiretrovirals.
This analysis involved four groups:
⋅ Group A: 11 people whose salvage regimen included raltegravir but not darunavir or etravirine
⋅ Group B: 13 people who started darunavir/ritonavir with raltegravir
⋅ Group C: 6 people who started etravirine with darunavir/ritonavir and raltegravir
⋅ Group D: 5 people who started etravirine while already taking raltegravir and darunavir/ritonavir
In group D, 4 people added etravirine because they could not tolerate enfuvirtide and 1 added etravirine after maraviroc failure.
Group D had a higher average viral load than group C (4.8 versus 3.8 log, or about 65,000 versus 6000 copies) and a lower median CD4 count (97 versus 315). People in group D had been infected for a median of 20 years, compared with 16 years in group C.
Raltegravir trough concentrations averaged 260 ng/mL in group A, 285 ng/mL in group B, 330 ng/mL in group C, and 309 ng/mL in group D. No between-group differences were statistically significant for raltegravir. Comparing darunavir troughs in groups B, C, and D, Tommasi found a significantly higher average level in group D (4633 ng/mL) than in group B (3039 ng/mL) (P = 0.04). Darunavir trough in group C (4205 ng/mL) was equivalent to that in group D (4633 ng/mL) (P = 0.7).
Average etravirine trough concentration was significantly higher in group D (719 ng/mL) than in group C (380 ng/mL) (P = 0.005). For comparison, median etravirine trough in 29 French patients starting the same doses of etravirine, darunavir, and raltegravir together was 275 ng/mL [2]. And in the DUET trials of etravirine and simultaneously started darunavir/ritonavir, median etravirine trough measured 299 ng/mL [3,4].
Raltegravir, darunavir, and etravirine troughs did not differ significantly between men and women.
Tommasi proposed that the difference between etravirine troughs in groups C and D can be explained by the opposite effects of etravirine and darunavir/ritonavir on the CYP3A4 drug-metabolizing enzyme. Etravirine induces CYP3A4 while darunavir/ritonavir inhibits it. When the drugs begin at the same time, she proposed, the inhibiting and inducing effects balance each other. But when a person starts etravirine while already taking darunavir/ritonavir, the inhibitory effect of darunavir prevails and troughs of both etravirine and darunavir rise.
Whether these differing etravirine trough concentrations have any clinical relevance is impossible to say. As Tommasi noted, etravirine troughs in healthy volunteers without HIV average 373 ng/mL, a value exceeded by both group C and group D. Thomas Kakuda of Tibotec, etravirine's maker, noted that interpatient variability and intrapatient variability of etravirine are high (60% and 40%), and that variability could affect results in a comparison of 6 versus 5 patients.
References
1. Tommasi C, Tempestilli M, Bellagamba R, et al. Pharmacokinetics of darunavir/ritonavir, raltegravir and etravirine co-administered in HIV-1 infected patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract O_11.
2. Muret P, Montange D, Kantelip J, Hoen B. Inter- and intra-variability of minimal concentration of Raltegravir, Etravirine and boosted Darunavir when used in combination as salvage therapy in experienced pre treated HIV patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract P_34.
3. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
4. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
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