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  13th International Workshop on Clinical Pharmacology of HIV Therapy
Barcelona, Spain
April 16-18, 2012
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Raltegravir 400 mg Once Daily With Atazanavir/Ritonavir Plus 2 NRTIs
  International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona
Mark Mascolini
Taken once daily at 400 mg, the integrase inhibitor raltegravir yielded adequate plasma concentrations in most pilot-study patients when combined with standard-dose atazanavir/ritonavir and two nucleos(t)ides (NRTIs), sometimes tenofovir [1]. All atazanavir trough concentrations lay above 150 ng/mL.
Raltegravir is licensed at a dose of 400 mg twice daily for antiretroviral-naive or experienced patients. A phase 2 dose-finding study in antiretroviral-naive people found equivalent 48-week virologic and CD4 responses with 100, 200, 400, or 600 mg of raltegravir twice daily [2]. Atazanavir boosts raltegravir levels 40% to 72%, probably by inhibiting raltegravir metabolism via UGT1A1.
To see whether once-daily raltegravir would provide adequate concentrations of the integrase inhibitor when combined with once-daily atazanavir/ritonavir plus two NRTIs, University of Torino investigators planned this pilot phase 2 study in people already taking 300/100 mg of atazanavir/ritonavir once daily.
Study participants added 400 mg of raltegravir once daily to their regimen. On day 10 the investigators collected plasma samples before dosing and 1.5, 3, 4.5, 6, 8, 12, and 24 hours after a morning dose. They calculated estimated glomerular filtration rates (eGFR) by the Cockrauft-Gault formula.
The Torino team enrolled 8 patients but excluded 2 from the analysis because they did not take either ritonavir or their NRTIs at some point in the study. Of the 6 remaining people, 3 were taking abacavir/lamivudine and 3 tenofovir/emtricitabine. Tenofovir lowers atazanavir concentrations.
The six participants were all men with a median age of 48.5 years (interquartile range [IQR] 48 to 62) and a median body mass index of 21.8 kg/m(2) (IQR 19.3 to 24.4). Median plasma creatinine and eGFR were 1.01 mg/dL (IQR 0.97 to 1.32) and 69.3 mL/min/24h (IQR 67.7 to 72.8). Everyone had a viral load below 20 copies. One person was HCV positive but had no hepatic impairment. The others had no liver, kidney, or gastrointestinal disease.
On day 10 raltegravir area under the concentration-time curve (AUC) averaged 14,497 ng*h/mL (90% confidence interval [CI] 13845 to 28325), maximum concentration (Cmax) 3984 ng/mL (90% CI 3863 to 6703), 24-hour concentration (C24) 40 ng/mL (90% CI 22 to 51), half-life 2.8 hours (90% CI 2.7 to 3.6), and clearance 27.1 L/h (90% CI 15.7 to 28.9). Raltegravir predose concentration and C24 were below the limit of detection in 1 of 6 patients (and below the 95% inhibitory concentration of 15 ng/mL).
Raltegravir 0-24-hour AUC with 400 mg once daily was similar to AUC0-24 with 800 mg once daily in the QDMARK study (14,895 ng*h/mL) and 2-fold higher than previously reported AUC0-12 with 400 mg twice daily (6340 to 6910 ng*h/mL). QDMRK found a significantly lower 48-week sub-50-copy response rate with 800 mg of raltegravir once daily than with 400 mg twice daily, 83% versus 89%, leading the investigators to conclude that "once-daily raltegravir [as the main drug in a regimen] cannot be recommended in place of twice-daily dosing." [3])
On day 10 atazanavir AUC averaged 26,414 ng*h/mL (90% CI 23,037 to 33,109), Cmax 2284 ng/mL (90% CI 1706 to 2666), C24 526 ng/mL (397 to 604), half-life 11.3 hours (90% CI 9.4 to 13.6), and clearance 11.4 L/h (9.2 to 13.1). Respective ritonavir values were 9147 ng*h/mL (8052 to 12,860), 1107 ng/mL (983 to 1244), 99 ng/mL (61 to 183), 5.5 hours (4.8 to 6.1), and 11 L/h (7.9 to 12). Atazanavir concentrations were comparable to those in historical controls and all troughs lay above the target of 150 ng/mL.
The Torino team proposed that "raltegravir 400 mg once daily associated with atazanavir/ritonavir warrants further investigation as a potential strategy in selected patients."
1. Calcagno A, D'Avolio A, Simiele M, et al. Pharmacokinetics of raltegravir 400 mg once-daily in combination with atazanavir/ritonavir plus two NRTIs. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract P_05.
2. Markowitz M, Nguyen BY, Gotuzzo E, et al, Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007;46:125-133.
3. Eron JJ Jr, Rockstroh JK, Reynes J, et al. QDMRK Investigators. 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;11:907-915. Erratum in Lancet Infect Dis. 2011;11:895.