Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

OBJECTIVE: We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4 years old after liver transplantation and to develop individualized tacrolimus dosing software. METHODS: A total of 663 blood concentrations from 85 patients aged 4.57 months to 3.97 years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. RESULTS: A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). CONCLUSIONS: A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA-24 with Tumor-Selective Toxicity.

BACKGROUND: Breast cancer is a commonly diagnosed cancer worldwide. Human MutT homolog 1 (MTH1) is found to be elevated in breast tumors and cancer cells need MTH1 for survival. Pharmacological inhibition of MTH1 may be potentially beneficial in the treatment of breast cancer. METHODS: MA-24 was screened by malachite green colorimetric assay for MTH1 inhibitors and the kinetic characteristics of MA-24 were assessed. The features of MA-24's binding with MTH1 were ascertained through molecular docking, and the cytotoxic activity of MA-24 was validated in vitro and in vivo. Target engagement assays, comet assay, and Western blot confirmed the intracellular target and mechanism of MA-24. RESULTS: MA-24 shows potent antitumor bioactivity both in vitro and in vivo. MA-24 competitively inhibited the MTH1 and further induced DNA strand breaks, leading to increased apoptosis of cancer cells depending on the upregulation of the cleaved-caspase 3-cleaved-PARP axis. In particular, MA-24 exhibited a powerful efficacy and safety in vivo (tumor growth inhibition rate: 61.8%). CONCLUSIONS: MA-24 possesses a broad spectrum of breast cancer cytotoxicity and offered valuable insights for overcoming the challenges of chemotherapy-related toxicity, which holds great potential for the further development MA-24 as an anti-cancer drug.

Population pharmacokinetics of oxcarbazepine 10-monohydroxy derivative in Chinese adult epileptic patients.

OBJECTIVE: Oxcarbazepine (OXC) is metabolised to active 10-monohydroxy derivative (MHD) after oral administration. Using this fact we aimed to develop an MHD population pharmacokinetic (PPK) model in Chinese adult epileptic patients to facilitate the clinical implementation of model-guided individualised drug therapy. METHODS: We collected blood samples from Chinese adult epileptic patients taking OXC at the Second Affiliated Hospital of Zhejiang University School of Medicine. We used high performance liquid chromatography (HPLC-MS/MS) with tandem mass spectrometry to detect MHD concentrations in the blood samples. We collected various data from patients including their demographic, pathological, and physiological information. MassARRAY method was used to detect ABCC2, ABCB1, SCN8A, SCN1A, SCN2A, SCN3A, UGT1A9, and UGT2B7 gene polymorphisms. We used a nonlinear mixed-effects modelling method to develop the PPK model and we predicted dosing regimens through simulation. RESULT: In total we collected 164 blood samples from 118 patients. We found that a one-compartment model with first-order absorption better described the in vivo MHD pharmacokinetics. UGT2B7 gene (rs7439366) site mutation and the combined use of valproic acid enhanced the MHD clearance rate. We divided patients into groups based on the UGT2B7 genotype and whether they were also using valproic acid at the same time. Individualised OXC dosing regimens were proposed for different subgroups of patients. CONCLUSION: In Chinese adult epileptic patients, individualised drug administration can be facilitated using a PPK model of OXC. TRIAL REGISTRATION NUMBER: ChiCTR-OOC-17012141.

Impact of Azithromycin on Forsythiaside Pharmacokinetics in Rats: A Population Modeling Method.

OBJECTIVE: Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019 (COVID-19). In China, use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen (for them, forsythiaside is the active antiviral and antibacterial component) in combination with azithromycin is common for the treatment of pediatric pneumonia. It is important to understand the reason why the combination of these compounds is better than a single drug treatment. This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin. METHODS: Twelve male Sprague-Dawley rats were randomly divided into an experimental group (Forsythia suspensa extract and azithromycin) and a control group (a single dose of Forsythia suspensa extract in 5% glucose solution). Plasma samples were collected at scheduled time points, and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration. Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group. RESULTS: Compared with a single administration, the area under the curve and half-life of forsythiaside increased, and forsythiaside clearance decreased significantly after co-administration with azithromycin. The in vivo behavior of forsythiaside could be described by the one compartment model. The forsythiaside clearance decreased when combined with azithromycin. Visual evaluation and bootstrap results suggested that the final model was precise and stable. CONCLUSION: Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure. A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.

Population pharmacokinetics of sirolimus in Chinese adult liver transplant recipients: a retrospective study.

Considering the significant interindividual variability and a narrow therapeutic index, we aimed to determine the population pharmacokinetics (PPK) of sirolimus and identify the factors in Chinese adult liver transplant recipients.Data were retrospectively extracted from adult liver transplant recipients receiving sirolimus in our hospital. The trough blood concentration data, obtained from traditional therapeutic drug monitoring-based dose adjustments, were used to develop a population pharmacokinetic model by non-linear mixed-effects modelling (NONMEM). The effect of demographic features, biological characteristics and concomitant medications was measured. The final model was verified by visual prediction check (VPC), bootstrap, and simulation.One hundred and sixteen blood concentrations from 63 patients were analysed. The PPK of sirolimus could be described by a one-compartment model with first-order absorption. Covariate analysis indicated that voriconazole co-therapy significantly decreased the oral clearance (CL) of sirolimus. The results of VPC and Bootstrap demonstrated that the final pharmacokinetic model adequately predicted observed concentrations. The simulation results showed that the dosage regimen of sirolimus should be reduced to 0.25 ∼ 0.45 mg/day for adult liver transplant recipients co-administered with voriconazole. The present study developed and validated a sirolimus PPK model for Chinese adult liver transplant recipients, and voriconazole co-therapy was found to be a significant covariate in the model. These results provide important information for clinicians to optimise the treatment regimens of sirolimus in Chinese adult liver transplant recipients.

Adverse Events During Pregnancy Associated With Entecavir and Adefovir: New Insights From a Real-World Analysis of Cases Reported to FDA Adverse Event Reporting System.

Background: Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring. Objective: To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP). Methods: Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1. Results: A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09-2.30) and 2.13 (95% CI, 1.04-4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54-8.18) and 2.85 (95% CI, 1.15-7.08), respectively. Conclusion: We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice.