Food and Sex-Related Impacts on the Pharmacokinetics of a Single-Dose of Ginsenoside Compound K in Healthy Subjects

Abstract

Background and Objectives: Ginsenoside compound K (CK) is a candidate drug for rheumatoid arthritis therapy. This clinical trial was designed to evaluate the effects of food and sex on the pharmacokinetics of CK and its metabolite 20(S)-protopanaxadiol (PPD).Methods: An open-label, single-center, two-period crossover trial was performed in healthy Chinese subjects (n = 24; male = 12, female = 12), randomized to either the fasting overnight or the high-fat meal group before a single 200 mg dose of monomer CK was administered. According to the concentration-time data of plasma and urine samples from each subject, the pharmacokinetic parameters of CK and 20(S)-PPD were calculated and statistically analyzed.Results: A two-way ANOVA test combined with mean plots showed no statistically significant interaction between food and sex. High-fat meal accelerated the absorption of CK, with tmax being shortened from 3.6 to 2.5 h (p = 0.015). In contrast, food significantly increased the Cmax, AUClast, and AUCinf(p < 0.001) with the 90% confidence intervals falling outside of the conventional 0.80–1.25. Females had higher exposure levels of CK than males, but the difference was statistically significant only after a high-fat meal. Of note, CK was rarely excreted in urine. Furthermore, the effects of food and sex were also observed on 20(S)-PPD.Conclusion: High-fat food and sex both had an impact on the disposition of CK in vivo, but rather than a significant interaction effect. High-fat food accelerated and increased the absorption of CK, while the exposure of CK was higher in females compared to males. The results indicate that food and sex should be two noteworthy factors in future research on CK.

Single- and Multiple-Dose Trials to Determine the Pharmacokinetics, Safety, Tolerability, and Sex Effect of Oral Ginsenoside Compound K in Healthy Chinese Volunteers

“…Unfortunately, due to the difficulties in distinguishing intestinal segments and inconsistency among protein levels, mRNA levels, and activities, the sex-related expression of transporters in the intestine still remains controversial (MacLean et al, 2008 ; Mariana et al, 2011 ). Another phenomenon that we could observe from these two trials was that food can significantly increase the absorption of CK, which was consistent with the results from another independent clinical trial (Chen et al, 2017 ). The exact mechanism for the increased ginsenoside CK exposure in the presence of a high-fat meal is still unknown and may be the result of increasing solubilization and dissolution in the intestinal fluids, especially, for the drugs with poor water solubility (Welling, 1996 ).…”

“…This work and what we've already published (Chen et al, 2017 ) both belong to phase I clinical trials of Ginsenoside Compound K Tablets (Hisun Pharmaceutical Co., Ltd, Taizhou, China), but they are completely independent trials. More concretely, these two studies were performed on different subjects through different designs for different purposes.…”

“…Our previous study results revealed that CK exposure in females was significantly higher than in males after oral administration (Supplementary Figures 1 , 2 and Supplementary Table 1 ), and pharmacokinetics data in rats suggested that the sex dimorphism mainly happened in the absorption phase of CK. Another clinical trial (registration number ChiCTR-IPR-15005787), designed to evaluate the effects of food and sex on the pharmacokinetics of CK, confirmed that its PK property was sex-related, and this dimorphism was independent from the food effect (Chen et al, 2017 ). We therefore hypothesized that intestinal transporters play a major role in CK mechanism of action in vivo for the following reasons.…”

“…This dose-ascending study was to investigate the PK properties, safety and tolerability of CK, which help to determine the dose in clinical application. While the published one (Chen et al, 2017 ) was to evaluate the effects of food and sex on CK and PPD, which provides the basis for clinical medication and individual drug administration. Either of them is a key step of the research that goes into developing a new drug.…”

The Effects of Ginsenoside Compound K Against Epilepsy by Enhancing the γ-Aminobutyric Acid Signaling Pathway

“…Our previous research has shown that GCK is safe and well-tolerated for healthy Chinese volunteers, where it exhibits a good pharmacokinetic profiles at a moderate dose ( Chen et al, 2018 ). Its pharmacokinetic properties are affected by food and gender in humans ( Chen et al, 2017 ). These findings indicated that GCK has a promising druggability that provides guidance for the development of CK.…”