Is it appropriate regarding patient preference to take Myrtol standardized enteric-coated soft capsules after a meal rather than at fasted state? A food-drug pharmacokinetic interaction study in healthy Chinese volunteers.

BACKGROUND: According to prescribing information for Myrtol standardized enteric-coated soft capsules, the medicine should be taken on an empty stomach. Some patients may experience stomach discomfort after oral administration in fasted state and would prefer to take the medicine after a meal. However, there is no literature addressing the effect of meal on absorption of this drug; therefore, it is desirable to explore the feasibility of taking the capsule after a meal from pharmacokinetic perspective.

METHODS: A gas chromatography coupled with triple quadruples mass spectrometry assay was established and validated for determining plasma concentrations of eucalyptol, a target component of Myrtol standardized capsules. A self-control clinical study was carried out in healthy male volunteers in fasted and fed states after a single oral dose of 300 mg capsules. Comparison of pharmacokinetic parameters in the two phases and bioequivalence evaluation were performed.

RESULTS: The specificity, sensitivity, accuracy, and precision of the assay satisfied the requirements for biopharmaceutical analysis. Pharmacokinetic parameters of eucalyptol (fasted vs fed) were as follows: maximal plasma concentrations (Cmax) (167.60±114.69 vs 518.89±314.47 ng·mL(-1)), time of maximum concentration (Tmax) (3.7±1.1 vs 4.8±0.7 h), elimination half-life (T1/2) (3.2±1.4 vs 2.6±0.7 h), area under the plasma concentration-time curve (AUC0-t) (584.91±369.90 vs 1,271.61±605.82 ng·h·mL(-1)), and AUC0-∞ (690.36±467.26 vs 1,458.02±720.21 ng·h·mL(-1)). There was statistically significant difference in Cmax, AUC0-t, and AUC0-∞ between the two dosing methods (P<0.05). Pharmacokinetic parameters of eucalyptol given in fasted state in Chinese were comparable to those in Germany population. The 90% confidence intervals for the ratio of Cmax (18.4%~64.7%), AUC0-t (28.9%~68.5%), and AUC0-∞ (31.1%~68.4%) values for the test (fasted) and reference (fed) were beyond the Food and Drug Administration's acceptable range of 80%~125%. In addition, significant difference was obtained in Tmax (P<0.05).

CONCLUSION: Compared with dosing at fasted state, taking Myrtol standardized capsules after a meal achieves a delayed absorption rate and an increased absorption extent. The two dosing methods were not bioequivalent in this small study and, thus, not interchangeable. Patient preference and pharmacokinetic food-drug interaction issue should be balanced. Further clinical study is necessary to explore the clinical outcome of oral administration of Myrtol standardized capsules after or with meal.