Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects.

STUDY OBJECTIVE

. To determine the influence of Echinacea purpurea on the pharmacokinetics of lopinavir-ritonavir and on cytochrome P450 (CYP) 3A and P-glycoprotein activity by using the probe substrates midazolam and fexofenadine, respectively.

DESIGN

Open-label, single-sequence pharmacokinetic study.

SETTING

Outpatient clinic in a federal government research center.

SUBJECTS

Thirteen healthy volunteers (eight men, five women).

INTERVENTION

Subjects received lopinavir 400 mg-ritonavir 100 mg twice/day with meals for 29.5 days. On day 16, subjects received E. purpurea 500 mg 3 times/day for 28 days: 14 days in combination with lopinavir-ritonavir and 14 days of E. purpurea alone. In order to assess CYP3A and P-glycoprotein activity, subjects received single oral doses of midazolam 8 mg and fexofenadine 120 mg, respectively, before and after the 28 days of E. purpurea.

MEASUREMENTS AND MAIN RESULTS

On days 15 and 30 of lopinavir-ritonavir administration (before and after E. purpurea administration, respectively), serial blood samples were collected over 12 hours to determine lopinavir and ritonavir concentrations and subsequent pharmacokinetic parameters by using noncompartmental methods. Neither lopinavir nor ritonavir pharmacokinetics were significantly altered by 14 days of E. purpurea coadministration. The post-echinacea: pre-echinacea geometric mean ratios (GMRs) for lopinavir area under the concentration-time curve (AUC) from 0-12 hours and for maximum concentration were 0.96 (90% confidence interval [CI] 0.83-1.10, p=0.82) and 1.00 (90% CI 0.88-1.12, p=0.72), respectively. Conversely, GMRs for midazolam AUC from time zero extrapolated to infinity and oral clearance were 0.73 (90% CI 0.61-0.85, p=0.008) and 1.37 (90% CI 1.10-1.63, p=0.02), respectively. Fexofenadine pharmacokinetics did not significantly differ before and after E. purpurea administration (p>0.05).

CONCLUSION

Echinacea purpurea induced CYP3A activity but did not alter lopinavir concentrations, most likely due to the presence of the potent CYP3A inhibitor, ritonavir. Echinacea purpurea is unlikely to alter the pharmacokinetics of ritonavir-boosted protease inhibitors but may cause modest decreases in plasma concentrations of other CYP3A substrates.