Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine

Abstract

The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.

Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro–In Silico Testing Strategy

“…[36] This implies that interindividual differences are not reflected. To account for interindividual variability in AFB1 kinetics, combining the PBK modeling with Monte Carlo analysis as recently done by Ning et al to predict interindividual variation in bioactivation and liver toxicity of lasiocarpine [71] could be considered in a future study.…”

The Role of Kinetics as Key Determinant in Toxicity of Pyrrolizidine Alkaloids and Their N-Oxides

“…Subsequent benchmark dose (BMD) modeling can be applied on the predicted in vivo dose-response data, enabling definition of a point of departure (PoD) for risk assessment, such as a BMDL x (the lower confidence limit of the benchmark dose causing an x% effect above background level) and BMDUx (the upper confidence limit of the benchmark dose causing an x% effect above background level). PBK modelling has recently been applied to describe the kinetics of three PAs, including riddelliine, lasiocarpine and monocrotaline [20,[26][27][28][29]. ▶ Fig.…”

Patient-Derived Xenografts as an Innovative Surrogate Tumor Model for the Investigation of Health Disparities in Triple Negative Breast Cancer

“…Distinguishing between interindividual and ethnic variation is important in oncology research, especially in testing drug response and pharmacokinetic studies. [81][82][83][84][85] Examining biomarker expression in larger cohorts of patients, or using meta-analyses, can help reduce the risk of this confounding effect. 81,86 As one study concluded, thousands of samples are required to accurately contribute gene lists for predicting outcome in cancer.…”

“…89 Attempts through computational analyses and algorithms have been made to address the role of interindividual variation in population studies. 84,[86][87][88] We propose that these analyses must be applied in studies examining ethnic variation in TNBC. Given the limitation of TNBC PDX models that represent ethnic patients, more established models are required to draw accurate conclusions with respect to ethnic variation in TNBC.…”