Darunavir/ritonavir and raltegravir coadministered in routine clinical practice: Potential role for an unexpected drug interaction

Abstract

The present study aimed to investigate potential drug interactions between darunavir and raltegravir in patients treated for HIV infection. We enrolled HIV-infected subjects on darunavir-containing regimens that underwent measurement of plasma darunavir trough concentration (12 ± 3 h after dosing). Two groups of patients were compared: those taking darunavir plus a nucleoside/nucleotide backbone (group 1) or a backbone + raltegravir (group 2). Interindividual pharmacokinetic variability was evaluated through the coefficient of variation (CV inter). We obtained 156 plasma samples from 63 patients, of which 44 in group 1 and 19 in group 2. Overall, darunavir geometric mean concentration was 2.90 mg/L (95% CI 2.34–3.60) while ritonavir geometric mean concentration was 0.21 mg/L (95% CI 0.17–0.27). We observed a high inter-individual variability in darunavir (CV inter 59%) and ritonavir (CV inter 103%) plasma levels. Darunavir concentration correlated with concomitant ritonavir levels ( r = 0.476, p < 0.001). Patients in group 1 had a higher darunavir geometric mean concentration than those in group 2 [3.44 mg/L (95% CI 2.79–4.23) versus 1.95 mg/L (95% CI 1.19–3.20), p = 0.017]. However, the proportion of subjects with concomitant HIV-RNA <50 copies/mL was higher in group 2 (78.9% versus 47.7%, p = 0.028). In a multivariable model, raltegravir co-administration was independently related to a lower darunavir concentration (mean difference −0.25 log 10 mg/L, 95% CI −0.46/−0.04, p = 0.020) after adjusting for time from last drug intake and concomitant drugs used. In conclusion, a potential drug interaction between darunavir and raltegravir was observed, although this did not seem virologically significant. For the distinct metabolic pathways of these drugs, its mechanism remains to be determined.