Drug Cocktail Interaction Study on the Effect of the Orally Administered Lavender Oil Preparation Silexan on Cytochrome P450 Enzymes in Healthy Volunteers

Abstract

This cocktail study evaluated the interaction potential of the oral lavender oil preparation silexan with major P450 (cytochrome P450) enzymes. Subjects and Methods: Sixteen healthy male or female Caucasians completed this double-blind, randomized, 2-fold crossover study. Silexan (160 mg) or placebo were administered once daily for 11 days. Additionally, on day 11 of both study periods, 150 mg caffeine (CYP1A2), 125 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan-HBr (CYP2D6), and 2 mg midazolam (CYP3A4) were administered orally. Formal interaction was excluded if the 90% confidence interval (CI) for the silexan over placebo ratios for phenotyping metrics (primary: AUC 0-t ) was within a 0.70-1.43 range. Results: According to the AUC 0-t comparisons, silexan had no relevant effect on CYP1A2, 2C9, 2D6, and 3A4 activity. Secondary phenotyping metrics confirmed this result. Mean ratios for all omeprazole-derived metrics were close to unity. The 90% CI for the AUC 0-t ratio of omeprazole but not for omeprazole/5-OH-omeprazole plasma ratio 3 hours post-dose or omeprazole/5-OH-omeprazole AUC 0-t ratio (secondary CYP2C19 metrics) was above the predefined threshold of 1.43, probably caused by the inherent high variability of omeprazole pharmacokinetics. Silexan and the phenotyping drugs were well tolerated. Repeated silexan (160 mg/day) administration has no clinically relevant inhibitory or inducing effects on the CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes in vivo.

No Clinically Relevant Interactions of St. John's Wort Extract Ze 117 Low in Hyperforin With Cytochrome P450 Enzymes and P‐glycoprotein

“…PK interaction was excluded when the 90% CIs for the geometric mean ratios were within the bioequivalence limits of 80–125% or the extended bioequivalence limits of 70–143%, also accepted for phenotyping metrics …”

“…A sample size of 16 participants allowed a rejection of each null hypothesis “interaction present induction/inhibition” with α = 0.05 (one‐sided) and a power of at least 99% for a tolerance zone of 0.50–2.0 assuming as a conservative approach that the intra‐individual CVs exceed 30% and the true ratio of μ test /μ reference = 1.0 . A sample size of 16 participants allowed a rejection of each null hypothesis “interaction present induction/inhibition” with α = 0.05 (one‐sided) and a power of at least 90% for a tolerance zone of 0.70–1.43 assuming that the intra‐individual CVs exceed 30% and the true ratio of μ test /μ reference = 1.0 . As a safety margin, an additional four participants were included to account for dropouts, resulting in a total sample size of N = 20.…”

Dicloxacillin induces CYP2C19, CYP2C9 and CYP3A4 in vivo and in vitro

“…As (S)‐warfarin (the most pharmacologically active isomer of racemic warfarin) is metabolized by CYP2C9, we added tolbutamide, a well‐validated substrate and biomarker for CYP2C9 metabolism , to the cocktail. This combination of biomarker drugs has previously been validated and used to evaluate the changes in drug metabolism caused by drug–drug interactions .…”

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

“…A lack of such information could be remedied by additional experiments, using redundant information provided by other components of the cocktail or choosing the most appropriate metabolite. The CIME combination was therefore designed to study the pooled activity of OATP1B1 & 1B3, the pooled activity of UGT 1A1, 1A6, 1A9 & 2B15, and the activity of P-glycoprotein and of CYP2C8, by the addition of rosuvastatin, acetaminophen (acetaminophen glucuronide), digoxin and repaglinide (M4-hydroxy-repaglinide), respectively, to a widely used more conventional cocktail composed of caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A) (Tomalik-Scharte et al 2010;Wohlfarth et al 2012;Doroshyenko et al 2013). Finally, we added memantine to the CIME combination to study the renal excretion of drugs (active tubular secretion), since the plasma pharmacokinetics of memantine correlates with urine pH and memantine is not metabolized (Freudenthaler et al 1998).…”