Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers

Objectives To evaluate the effect of a low- and high-fat meal and co-administration of ranitidine or omeprazole on the pharmacokinetics of ritonavir-boosted danoprevir (DNVr). Methods In this randomised, open-label, cross-over study, healthy subjects received a single dose of DNVr. In group 1, DNVr was administered while fasting or with a low-fat or high-fat meal. In group 2, DNVr was administered alone or with ranitidine 150 mg (single dose) or omeprazole 40 mg (multiple doses). Key findings Group 1 (n = 16): relative to fasting conditions, food slightly prolonged absorption but did not alter the extent of absorption. DNV area under the plasma concentration-time curve extrapolated to infinity (AUC_0-∞), maximum plasma concentration (C_max), and plasma concentration 12 h after administration (C_12h) geometric mean ratios (GMR%) (90% confidence interval (CI)) with a low-fat meal were 92.3 (80.2-106), 61.8 (51.0-74.9) and 95.2 (80.9-112), versus fasting conditions, and with a high-fat meal 99.5 (86.4-115), 58.9 (48.5-71.6) and 101 (86.0-119). Group 2 (n = 13): ranitidine or omeprazole had no clinically significant effect on DNV pharmacokinetics. DNV AUC_0-∞, C_max and C_12h GMR% (90% CI) with ranitidine: 81.9 (68.3-98.1), 104 (86.9-123) and 87.5 (69.3-111), and with omeprazole: 83.0 (67.4-102), 92.7 (70.6-122) and 93.3 (65.6-133). Conclusions The absence of clinically relevant effects of food, ranitidine or omeprazole on DNVr pharmacokinetics suggests that DNVr can be administered without regard to meals and in combination with H₂ antagonists or proton pump inhibitors.