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Application of a Backpropagation Artificial Neural Network in Predicting Plasma Concentration and Pharmacokinetic Parameters of Oral Single-Dose Rosuvastatin in Healthy Subjects.
Xu, Y, Lou, H, Chen, J, Jiang, B, Yang, D, Hu, Y, Ruan, Z
Clinical pharmacology in drug development. 2020;(7):867-875
Abstract
A backpropagation artificial neural network (BPANN) model was established for the prediction of the plasma concentration and pharmacokinetic parameters of rosuvastatin (RVST) in healthy subjects. The data (demographic characteristics and results of clinical laboratory tests) were collected from 4 bioequivalence studies using reference 10-mg RVST calcium tablets. After the data were cleaned using extreme gradient boosting, 13 important factors were extracted to construct the BPANN model. The model was fully validated, and mean impact values (MIVs) were calculated. The model was used to predict the plasma concentration and pharmacokinetic parameters of oral single-dose RVST in healthy subjects under fasting and fed conditions. The predicted and measured values were compared in order to evaluate the accuracy of prediction. The constructed model performed well in validation. The top 3 factors ranked by MIV related to RVST concentration are fasting/fed, time, and creatinine clearance. The time-concentration profiles of the measured and predicted data agreed well. There were no significant differences (P > .05) in the area under the concentration-time curve from 0 to the last measurable concentration (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), half-time of elimination, peak concentration, and time to peak concentration of the measured data and data predicted by BPANN. The BPANN model has an accurate prediction ability and can be used to predict RVST concentration and pharmacokinetic parameters in healthy subjects.
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Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies.
Chen, J, Lou, H, Jiang, B, Shao, R, Yang, D, Hu, Y, Xu, Y, Ruan, Z
Clinical pharmacology in drug development. 2020;(2):235-245
Abstract
The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open-label, and 2-period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10-mg dose of rosuvastatin with a 7-day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high-fat and high-calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.
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Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function.
Perakakis, N, Upadhyay, J, Ghaly, W, Chen, J, Chrysafi, P, Anastasilakis, AD, Mantzoros, CS
Metabolism: clinical and experimental. 2018;:240-249
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Abstract
BACKGROUND We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. METHODS The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. RESULTS The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. CONCLUSIONS We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.
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Bioequivalence evaluation of cefdinir in healthy fasting subjects.
Chen, J, Jiang, B, Lou, H, Yu, L, Ruan, Z
Arzneimittel-Forschung. 2012;(1):9-13
Abstract
A simple and sensitive HPLC method was developed to determine cefdinir (CAS 91832-40-5) in human plasma. The method was validated by investigating the accuracy and precision for intra- and inter-day runs in a linear concentration from 0.05-2.0 µg/ml. The object of this study was to compare the bioavailability of cefdinir capsule (reference) and cefdinir granule (test) containing 100 mg of cefdinir. A randomized, open-label, single-dose, 2-way crossover bioequivalence study in 20 healthy, Chinese, male subjects was conducted. A 1-week wash-out period was applied. Blood samples were collected before and with 10 h after drug administration. The formulations were compared using the following pharmacokinetic parameters: AUC0-t, AUC0-∞ and C max. The 90% confidence interval (CI) of the ratios of log-transformed AUC0-t and AUC0-∞ were used to assess bioequivalence between the 2 formulations using the equivalence interval of 80 and 125%. The results showed that the 90% CI of the ratios of AUC0-t, AUC0-∞ and C max were 102.5% (94.7-111.0%), 103.4% (94.8-112.7%) and 106.4% (97.0-116.7%), respectively, which indicated 2 formulations of cefidinir are bioequivalent. Both treatments showed similar tolerability and safety.