(M1030-10-66) Integrating Herbal Medicine into Modern Practice: Nonclinical Evaluation of Cinnamomum cassia Extract and Extrapolation from Animals to Humans

Purpose: In several Asian countries, herbal remedies have been passed down for generations and generations to cure several illnesses. The global interest in herbal medicines has risen and its global market size was valued to be around 170 billion USD in 2022 [1]. Although indicated by long years of its usage, the evidence-based assessment of safety and efficacy has always been a challenge in non-clinical and clinical research of herbal medicines since it is hard to name its "active ingredients" and plasma concentrations of bioactive components are hard to detect [2]. Therefore, pharmaco(toxico)kinetic studies of herbal medicines were often omitted. However, over the years, the detection of bioactive components in biomatrix has become possible with the help of advancement in analytical technique. Moreover, the FDA guidance on botanical drug development recommends attempting to measure blood levels of active constituents at nonclinical and clinical phase, if they are known [3]. Recently, an herbal medicine made of CKD-495, a dried powder of Cinnamomum cassia extract (CCE), has been approved in the Republic of Korea. However, until now, pharmacokinetic study on CKD-495 was not conducted as it is not a prerequisite for approval of herbal medicine in Korea. Therefore, this study aims to conduct non-clinical evaluation on major bioactive constituents of CCE, a commonly used ingredient in traditional herbal medicine in Asia, and to predict their plasma concentrations in humans using extrapolation to provide scientific-evidence for the herbal medicine.

Methods: A pharmacokinetic study of the major components of CCE, cinnamic acid (CA), ferulic acid (FA), 3,4-dihydroxybenzaldehyde (3,4-DHBA) and 4-hydroxycinnamaldehyde (4-HCA), was conducted in male Sprague Dawley rats. Low (24 mg/kg), mid (75 mg/kg), and high (240 mg/kg) doses of CKD-495 were orally administered to 15 SD rats (n=5). The blood was sampled at 0, 5, 10, 20, 30, 45, minutes and 1, 2, 4, 8, 12, 24 hours after the administration, and 7 organs including brain, kidney, liver, lung heart, stomach and small intestine were extracted at 24 hours after the administration. Novel bioanalysis methods for the compounds were developed and validated in plasma and tissues according to the FDA guidance. Phoenix WinNonlin (Certara^TM Company, version 8.3) was used for the analysis of pharmacokinetic data and compartmental modeling. Then allometric scaling was applied to extrapolate pharmacokinetic parameters of the four bioactive components from rats to humans for prediction of human plasma concentration.

Results: The developed bioanalytical method has met the criteria of FDA guidance in all biomatrices. After 24 hours of oral administration, CA was mostly distributed in intestine, brain, kidney and liver; FA was mostly distributed in intestine, kidney and lung; 3,4-DHBA was mostly distributed in stomach, intestine and kidney; and 4-HCA was mostly distributed in liver. The temporal plasma concentration profiles of CA and 4-HCA were obtained in low, medium and high dose groups, but FA and 3,4-DHBA were quantitated at only few time points in high-dose groups. The average T_max was 0.05±0.01 hour and 0.12±0.04 hour for CA and 4-HCA, respectively. The C_max and AUC_last of CA and 4-HCA increased in dose-proportional manner. The plasma profiles of CA were best described by two-compartmental model with linear absorption and elimination using multiplicative error, whereas the plasma profiles of 4-HCA were best described by one-compartment model with linear absorption and elimination using additive and multiplicative error. Using the optimal model, pharmacokinetic parameters including absorption rate constant (K_a), volume of distribution (V) and clearance (CL) were estimated. Then human plasma concentration profiles for CA and 4-HCA were predicted using one-species simple allometry. The estimated Cmax and AUCinf of the predicted profiles were between 45.51 ~136. 55 ng/mL, 66~198.45 ng*h/mL and 0.07~ 0.20 ng/mL, 0.35~1.06 ng*h/mL for CA and 4-HCA, respectively.

Conclusion: The tissue distribution and plasma concentration profiles of major bioactive components of CKD-495 were successfully captured using the novel bioanalysis method. After 24 hours, the major bioactive components of CKD-495 were mostly found in organs including stomach, intestine, brain, kidney and liver. The human plasma concentration profiles for two major bioactive components of CKD-495 were predicted using allometry from the pharmacokinetic model estimated rat parameters. This study provides fundamental scientific evidence for the approved herbal medicine and will facilitate its future safety and efficacy assessment.

References: [1] Fortune Business Insights. Herbal Medicine Market Size, Share & COVID-19 Impact Analysis. 2023.05.01. https://www.fortunebusinessinsights.com/herbal-medicine-market-106320.
[2]Park, Jin-Han. "Evidence-based herbal medicine in efficacy and safety assessments." Advances in Traditional Medicine 8.2 (2008): 103-110.
[3] Food and Drug Administration, Botanical drug development guidance for industry. Pharmaceutical Quality/CMC Revision, 2016. 1.

Acknowledgements:This study was supported by Chong Kun Dang pharmaceutical Corp. The authors declare no conflicts of interest.

The graphical abstract of "Integrating Herbal Medicine into Modern Practice: Nonclinical Evaluation of Cinnamomum cassia Extract and Extrapolation from Animals to Humans"