Pharmacokinetics of and Short-Term Virologic Response to Low-Dose 400-Milligram Once-Daily Raltegravir Maintenance Therapy

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) was 15.6 mg/liter-h and the minimum plasma drug concentration (C-trough) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC(0-24) was 33.6 mg/liter-h and the C-trough was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC(0-24) was 18.6 mg/liter-h and the C-trough was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC(0-24) for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC(0-24) and those on raltegravir at 400 mg QD had a similar AUC(0-24). More patients had a C-trough of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C-trough values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C-trough and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed.