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

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.