Non-compartmental data analysis using SimBiology and MATLAB

MATLAB® is widely used for numerical analysis, modeling, and simulation. One of MATLAB's tools, SimBiology®, is often used for pharmacokinetic, pharmacodynamic model and dynamic systems; however, SimBiology seems to be rarely used for non-compartmental analysis (NCA), and the published official documentation provides a poor description of the analysis algorithm for NCA. Therefore, we conducted NCAs with a hypothetical dataset and some scenarios and compared the results. According to the results of this study, SimBiology estimates parameters using the unweighted linear regression for the terminal slope and linear interpolation method. Moreover, although the documentation describing the actual analysis algorithm used to process non-numeric data is not easily accessible to users, users may introduce numeric data at time zero to perform NCA properly. Using the command window, users can perform analyses more quickly and effectively. If the NCA official documentation were improved, SimBiology might be more widely adopted to perform NCA in clinical pharmacology.

Development of R packages: ‘NonCompart’ and ‘ncar’ for noncompartmental analysis (NCA)

Noncompartmental analysis (NCA) is a primary analytical approach for pharmacokinetic studies, and its parameters act as decision criteria in bioequivalent studies. Currently, NCA is usually carried out by commercial softwares such as WinNonlin®. In this article, we introduce our newly-developed two R packages, NonCompart (NonCompartmental analysis for pharmacokinetic data) and ncar (NonCompartmental Analysis for pharmacokinetic Report), which can perform NCA and produce complete NCA reports in both pdf and rtf formats. These packages are compatible with CDISC (Clinical Data Interchange Standards Consortium) standard as well. We demonstrate how the results of WinNonlin® are reproduced and how NCA reports can be obtained. With these R packages, we aimed to help researchers carry out NCA and utilize the output for early stages of drug development process. These R packages are freely available for download from the CRAN repository.

Study on brain drug concentration of geniposide in mice after iv injected with Xingnaojing Injection and its pharmacokinetics / 中草药

Objective: To develop an HPLC method for the determination of geniposide concentration in mouse brain and to investigate the pharmacokinetics after iv injection of Xingnaojing Injection. Methods: Forty mice were iv injected with Xingnaojing Injection 18 mg/kg (by geniposide), and the brain samples were collected at 1, 3, 5, 10, 30, 60, 90, 120 min after eyeball bleeding and 5 mice were sacrificed by cervical dislocation. The whole brain of mice was separated quickly to prepare brain homogenates, and the concentration of geniposide was detected by HPLC. The pharmacokinetic parameters were calculated by the software of Kinetica and the fitting method was noncompartmental. Results: The calibration curve was in good linear in the range of 54-1620 ng/g, r=0.9991. The extraction recoveries of geniposide brain drug concentration at 216, 864, and 1620 ng/g were (102.60 ± 4.28)%, (102.16 ± 4.48)%, and (97.66 ± 3.25)%, respectively. And the RSD values of inter-and intra-day were below 4.10%. The pharmacokinetic parameters were that the Cmax was (1 246.0 ± 520.7) ng/g, the tmax was 1 min, the MRT was (50.5 ± 1.9) min, and the AUC was (35780.3 ± 6148.0) ng/(g·min). Conclusion: The HPLC method for determining geniposide concentration in brain is simple, rapid, sensitive, and suitable for pharmacokinetic studies.

Pharmacokinetics and Safety of Levodropropizine Controlled Release Tablet after Repeated Dosing in Healthy Male Volunteers

BACKGROUND: Levodropropizine is non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels. Currently, levodropropizine 60 mg is taken three-times daily. A controlled release formulation of levodropropizine (levodropropizine CR) 90 mg was developed, which can be taken twice daily. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of levodropropizine CR 90 mg tablets in healthy male volunteers. METHODS: A randomized, open-label, cross-over study was conducted in 24 healthy male volunteers. Each subject received levodropropizine syrup 60 mg three times daily or levodropropizine CR 90 mg twice daily for 3 days. Blood samples for pharmacokinetic analysis were collected pre-dose and up to 24 hours on day 4. Pharmacokinetic analysis was conducted by non-compartmental method. Safety assessments including monitoring adverse events, laboratory tests, vital signs, physical examinations and ECGs were performed throughout the study. RESULTS: A total of 20 male volunteers completed the study. The maximum steady-state plasma concentration (Css,max) of levodropropizine syrup and levodropropizine CR were 313.28 ng/mL and 285.31 ng/mL and time to reach Css,max (Tmax,ss) were 0.48 hr and 0.88 hr, respectively. The area under the concentration-time curve to the last measured concentration of two groups were 2345.36 hr x ng/mL and 2553.81 hr x ng/mL, respectively. There was no serious adverse event. CONCLUSION: Levodropropizine CR 90 mg tablet was safe and well-tolerated when administered twice daily for 3 days. No statistically significant differences were seen in Css,max and AUCss,24hr between the two formulations. This study provided pharmacokinetic evidences that the twice-daily dosing regimen of levodropropizine 90 mg may substitute the conventional 3-times-daily regimen of levodropropizine 60 mg.

Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in normal and dehydrated rabbits / 药学学报

Two different salts of diclofenac, diclofenac sodium and dielofenae potassium, in tablet dosage form were tested for their bioavailability and disposition kinetics in a group of eighteen rabbits in normal and experimentally induced dehydrated conditions with a wash out period of 7 days between both stages of study. Biochemical and physiological parameters were also measured in both normal and dehydrated states. Diclofenac levels in plasma were determined using a validated reversed phase HPLC method. Primary kinetic parameters i.e. AUC0-∞, Cmax, Tmax and other disposition kinetics were obtained with non-compartmental procedure. Biochemical parameters i.e. packed cell volume, plasma glucose and total lipid concentration in dehydrated rabbits increased significantly. Plasma concentration of diclofenac sodium and diclofenac potassium decreased significantly in water deprived rabbits. In comparison, diclofenac potassium in normal and dehydrated state of the same group of rabbits showed a significantly increased plasma concentration when compared with diclofenac sodium.