Intracellular raltegravir concentrations better with twice-daily than once-daily dosing

Mark Mascolini,

Intracellular concentrations of raltegravir stayed above the 95% effective concentration (EC95) in higher proportions of people taking this integrase inhibitor twice daily than in those taking it once daily, according to results of a 13-person study [1]. The average intracellular-to-plasma ratio was 0.37.

Raltegravir is licensed for adults at a dose of 400 mg twice daily with or without food. A randomised trial of twice- versus once-daily raltegravir for antiretroviral-naive people found that 318 of 382 (83%) in the once-daily group versus 343 of 386 (89%) in the twice-daily group had a viral load below 50 copies/mL after 48 weeks, a significant difference (-5.7%, 95% confidence interval -10.7 to -0.83, P = 0.044) [2]. The investigators concluded that “despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing.”

The study of plasma and intracellular raltegravir concentrations involved 12 people taking 400 mg of raltegravir twice daily and 1 taking 800 mg once daily for more than 1 week [1]. People on the twice-daily dose who had a viral load below 50 copies were offered a switch to once-daily dosing for at least 3 days so the investigators could assess raltegravir after once-daily dosing. Six people agreed.

In the twice-daily group, the researchers collected 26 paired samples of plasma and peripheral blood mononuclear cells (PBMCs) 2, 4 or 6, and 12 hours after dosing. In the once-daily group they collected 12 paired samples over the 24-hour dosing interval. Among people taking raltegravir twice daily, 3 had a detectable viral load; 2 of these were considered blips, and one load of 2649 copies came during the first 6 weeks of treatment.

No one taking raltegravir twice daily had a plasma trough concentration below the EC95 (14 ng/mL). Three of 12 had an intracellular trough below the EC95, at 7, 11.1, and 13.3 ng/mL.

Two of 6 people taking raltegravir once daily had a plasma trough below the EC95, at 7 and 13.8 ng/mL. Three of these 6 had an intracellular trough below the EC95, at 1.56, 4.06, and 6.56 ng/mL.

The mean ratio of intracellular-to-plasma concentrations was 0.37 and did not change over time. The ratio was higher than reported previously, probably because cell-wash steps in older methods flushed out some intracellular drug.

The researchers proposed that the high plasma and intracellular troughs with twice-daily raltegravir “may contribute to the efficacy observed with this regimen.”

UK researchers just published results of a 24-person study comparing plasma and intracellular raltegravir concentrations with once- and twice-daily dosing, with or without darunavir/ritonavir [3]. Study participants were taking 400 mg of raltegravir twice daily for at least 21 days. They added 800/100 mg of darunavir/ritonavir once daily for 14 days. During that 14-day period, people were randomised to continue twice-daily raltegravir (group 1) or to switch to 800 mg once daily (group 2).

Geometric mean ratios (and 90% confidence intervals) of raltegravir area under the concentration-time curve without and with darunavir/ritonavir for group 1 were 0.90 (0.73 to 1.44) in plasma and 1.02 (0.81 to 1.67) in cells and for group 2 were 1.21 (1.03 to 1.77) in plasma and 1.27 (1.07 to 1.94) in cells. These researchers concluded that “no remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen.”


  1. Sandkovsky US, Swindells S, Robbins BL, Nelson SR, Acosta EP, Fletcher CV. Measurement Of plasma and intracellular concentrations of raltegravir in patients with HIV infection. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract A1-1738b.
  2. Eron JJ Jr, Rockstroh JK, Reynes J, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011 Sep 19.
  3. Jackson A, Watson V, Back D, et al. Plasma and intracellular pharmacokinetics of darunavir/ritonavir once daily and raltegravir once and twice daily in HIV-infected individuals. J Acquir Immune Defic Syndr. 2011 Sep 15. Epub ahead of print.

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