Toxicokinetics

This is a draft paper for discussion. It does not reflect the views of the Committee and should not be cited.

22.             The EMA assessment reports on E. purpurea (EMA, 2014) and E. angustifolia (EMA, 2012) note that available pharmacokinetic data are limited and primarily focus on alkylamides and, to a lesser extent, caffeic acid conjugates.  According to the human pharmacokinetic studies reviewed in the EMA reports, the alkylamides from E. purpurea and E. angustifolia show good oral bioavailability with rapid absorption and measurable plasma concentration within 20 - 60 minutes post-ingestion. The reported peak plasma concentration Cmax values for alkylamides varied between studies from 0.04 ng/mL for E. purpurea alkylamides (Goey et al., 2012) to over 300 ng/mL for E. purpurea/E. angustifolia alkylamides (Matthias et al., 2005a). The EMA highlighted that these discrepancies are likely due to differences in the alkylamide profiles between Echinacea species, extract concentrations, analytical methods, and study design. Caffeic acid derivatives were not detected in plasma after oral administration and their oral bioavailability was questioned by the EMA assessors (EMA, 2014). The key pharmacokinetic studies from the EMA assessment reports are briefly outlined below.

E. purpurea

23.             In a small clinical study by Goey et al. (2012), three cancer patients (age and sex not specified) received 20 drops of a commercial E. purpurea extract (65% V/V ethanol extract of freshly harvested E. purpurea herb (drug extract ratio (DER) 1:12)) and roots (DER 1:11) three times daily for 14 days. After the dose in the morning of day 15, blood samples for pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (DTAI) were drawn at 0, 30, 60 and 120 min post dose.  For all three patients the plasma concentration–time curves showed a similar time course with a maximum plasma concentration of DTAI (0.04–0.18 ng/mL) achieved at 30 minutes after ingestion. The authors stated that the findings indicated low systemic exposure to alkylamides after repeated oral dosing.

E. angustifolia

24.             In a randomised, open-label, crossover study, 11 healthy subjects (5 men and 6 women aged 25–36 years) received a single oral 2.5 mL dose of a 60% ethanolic extract from E. angustifolia roots (Woelkart et al., 2005). The maximum plasma concentration of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (DTAI), the main alkylamides in E. angustifolia roots, of 10.88 ng/mL was reached at 30 minutes after the dose. The authors noted that highly lipophilic alkylamides with no double and triple bond at the end of the fatty acid chain could not be detected in the blood.

E. angustifolia/E. purpurea

25.             Eleven healthy volunteers, males and females aged 18-26 years received Echinacea orally (4 tablets, each containing extract equivalent to 675 mg of E. purpurea root plus 600 mg of E. angustifolia root prepared from the dried ethanolic extracts of the two Echinacea species, which equals to a total dose of 2,700 mg E.purpurea root and 2,400 mg E.augustifolia root) immediately after a high fat breakfast (n=9) or fasted state (n=2) (Matthias et al. 2005). Blood samples were taken prior to tablet ingestion as well as 0.33, 0.66, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4, 6, 8, 10, and 12 h post dose. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were rapidly absorbed and were measurable in plasma 20 min after tablet ingestion and remained detectable for up to 12 h. The maximal concentrations for the sum of alkylamides in human plasma were reached within 2.3 hours post ingestion and averaged 336 +/- 131 ng/mL plasma. The authors reported that the presence of food did not appear to influence the rate of alkylamide uptake, as plasma concentrations in the fasted state were within the range observed in subjects who consumed Echinacea after a standard high‑fat breakfast. They concluded that alkylamides from Echinacea preparations were orally bioavailable and their pharmacokinetics supported the three times daily regimen already recommended for Echinacea.