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  EACS - 12th European AIDS Conference
November 11-14, 2009
Cologne, Germany
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Lower Intracellular Carbovir (Abacavir) Levels With Darunavir/Ritonavir
  12th European AIDS Conference, November 11-13, 2009, Cologne, Germany
Mark Mascolini
Giving abacavir with darunavir/ritonavir lowered concentrations of abacavir in plasma 22% to 38%, while significantly slicing intracellular minimum concentrations of carbovir triphosphate (abacavir's active metabolite) in a pharmacokinetic study of people with HIV [1]. Both darunavir and raltegravir widened the variability of intracellular carbovir levels in this study from London's Chelsea and Westminster Hospital.
Akil Jackson and colleagues signed up adults already taking a regimen containing 600 mg of abacavir once daily plus two nucleosides (but not the nucleotide tenofovir). Everyone had a CD4 count above 100. The protocol excluded people with active illness, an AIDS condition, body mass index above 30 kg/m(2), viral load above 400 copies, or drugs that might interact with those being studied.
The researchers randomized them to add 900/100 mg of darunavir/ritonavir once daily or 400 mg of raltegravir twice daily for 15 days, then to switch to the opposite drug for another 15 days. The researchers measured abacavir and carbovir levels before people started either darunavir or raltegravir and continuously after the morning dose on the last day people were taking darunavir or raltegravir.
The 17 men and 2 women recruited averaged 44.6 years in age and had a median weight of 80.5 kg (standard deviation [SD] 21.8) and a median body mass index of 23.9 (SD 2.9). Median CD4 count stood at 582 and ranged from 227 to 1129. Everyone had a viral load below 50 copies. Fifteen study participants were Caucasian, 4 were African, and 1 was Chinese.
Abacavir plasma levels did not differ after 15 days of raltegravir, but they were lower after 15 days of darunavir/ritonavir. Geometric mean area under the concentration-time curve (AUC) fell from 13,536 to 9882 ng/h/mL with darunavir (90% confidence interval [CI] 12,277-16,278 before and 9062-11,812 with). Minimum concentration (Cmin) dropped 4.3 To 2.7 ng/mL (90% CI 3.9-4.7 before and 2.4-4.8 with). And maximum concentration (Cmax) fell from 3923 to 3115 ng/mL (90% CI 680-4537 before and 2901-3654 with).
Geometric mean ratios for abacavir with versus without darunavir/ritonavir were 0.73 for AUC (90% CI 0.67-0.80), 0.62 for Cmin (90% CI 0.51 to 0.67), and 0.78 for Cmax (90% CI 0.70-0.87). Darunavir, ritonavir, and raltegravir concentrations were similar to those in historical controls.
Intracellular carbovir Cmins were significantly lower when people took abacavir with darunavir than when they did not: geometric mean 107 ng/mL without darunavir (90% CI 96-143) and 76 ng/mL with darunavir (90% CI 71-144). The geometric mean ratio of carbovir Cmin when abacavir was taken with darunavir versus without darunavir was 0.68 (90% CI 0.48-0.95). Carbovir Cmin was not significantly lower with raltegravir.
Intracellular carbovir levels varied substantially more with darunavir codosing, and even more so with raltegravir. Without either darunavir or raltegravir, Cmin ranged from 35 to 299 ng/mL. With darunavir the Cmin range spanned 14 to 247 ng/mL, and with raltegravir the range was 6 to 327 ng/mL.
1. Jackson A, Gedela K, Dickinson L, et al. Pharmacokinetics of plasma abacavir in the absence and in the presence of darunavir/ritonavir or raltegravir in HIV-infected subjects. 12th European AIDS Conference. November 11-13, 2009. Cologne, Germany. Abstract PE4.