Drug-drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes.

Background: The effect of drug-drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. Objectives: To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes. Design: We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3). Methods: Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C0/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different. Results: In this study, the C0/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C0/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C0/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group. Conclusion: Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C0/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Differential drug interactions of caspofungin on tacrolimus in Chinese kidney transplant patients with different CYP3A5 genotypes Why was the study done? Currently, there have been studies reporting the effect of caspofungin on tacrolimus blood concentrations, but the conclusions are conflicting, and no study has focused on the effect of CYP3A5 genotypes on the drug-drug interaction. We explored a number of research questions: 1. Does caspofungin have an effect on the pharmacokinetics of the immunosuppressant tacrolimus? 2. How does CYP3A5*3, which affects tacrolimus metabolism significantly, affect tacrolimus blood concentration levels? 3. How should the dose of tacrolimus be adjusted when combined with caspofungin? What did the researchers do? By reviewing literature, we understood the problems related with the kidney transplant patients better, which led to the development of strict inclusion and exclusion criteria. The patients (from January 2015 to December 2022) were categorized into combination and non-combination groups according to whether they were co-administered with caspofungin or not. The results of the study were analyzed using SPSS 22.0. What did the researchers find? The study finally included 200 patients. We found no statistically significant differences in the dose-corrected trough concentrations (C₀/D) and dose requirements (D) of tacrolimus between the combination and non-combination groups. However, in patients with CYPA5*3/*3 genotype, tacrolimus C₀/D values were significantly lower in the combination group than in the non-combination group, and the required daily tacrolimus dose was increased. What do the findings mean? This study has found that co-administration of caspofungin in patients with CYP3A5*3/*3 genotype resulted in a significant decrease in the C₀/D value of tacrolimus, therefore, an appropriate increase in the daily dose of tacrolimus is recommended. The implication is that it is important and necessary to monitor the concentrations of tacrolimus and the CYP3A5 genotypes, and adjust the dose when combined or discontinuing with caspofungin in kidney transplant patients.

CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Voriconazole in Chinese Kidney Transplant Patients.

BACKGROUND: The effect of drug-drug interaction (DDI) between tacrolimus and voriconazole on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. OBJECTIVE: The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients. METHODS: All kidney transplant patients were divided into combination and non-combination groups based on whether tacrolimus was combined with or without voriconazole. Each group was subdivided into CYP3A5 expresser (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 nonexpresser (CYP3A5*3/*3). A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between combination and non-combination groups, respectively. Tacrolimus C0/D was also compared between CYP3A5 expresser and nonexpresser in both groups. RESULTS: The C0/D values of tacrolimus were significantly different between CYP3A5 expresser and nonexpresser in combination group (378.20 [219.38, 633.48] ng/mL/[mg/kg/d] vs 720.00 [595.35, 1681.50] ng/mL/[mg/kg/d], P = 0.0010). Either in CYP3A5 expresser or nonexpresser, we found a statistically significant difference in tacrolimus C0/D between combination and non-combination group (P < 0.0001). The increase in CYP3A5 nonexpresser was 1.38 times higher than that in CYP3A5 expresser (320.93% vs 232.19%). CONCLUSION AND RELEVANCE: The median C0/D values were 90.38% higher in kidney transplant recipients with CYP3A5*3/*3 genotype than in those with CYP3A5*1/*1 or CYP3A5*1/*3 genotype when treated with both tacrolimus and voriconazole. A CYP3A5 genotype-dependent DDI was found between tacrolimus and voriconazole. Therefore, personalized therapy accounting for CYP3A5 genotype detection and therapeutic drug monitoring is necessary for kidney transplant patients when treating with tacrolimus and voriconazole.

Association between GLP-1R gene polymorphism and dyslipidemia in Chinese patients with type 2 diabetes mellitus: A case-control study.

OBJECTIVE: To evaluate the relationship between GLP-1R gene polymorphisms and type 2 diabetes mellitus with dyslipidemia and without dyslipidemia in China. METHODS: A total of 200 patients with Type 2 Diabetes Mellitus (T2DM) were included in this study, including 115 with dyslipidemia and 85 without dyslipidemia. We used Sanger double deoxygenation terminal assay and PCR-RFLP to detect genotype of the GLP-1R rs10305420 and rs3765467 loci. T-test was used to analyze the association between gene polymorphisms and lipid indicators. SHEsis online analysis software was used to analyze the linkage balance effect of loci, and SPSS 26 was used to calculate the gene interaction by dominant model. RESULTS: The genotype distribution of the two loci in the sample of this study was in accordance with Hardy-weinberg equilibrium. There were significant differences in the genotype distribution and allele frequency of rs3765467 between T2DM patients with and without dyslipidemia (GG 52.9%, GA + AA 47.1% vs. GG 69.6%, GA + AA 30.4%; P = 0.017). Under the dominant model, the effects of rs3765467 A allele and rs10305420 T allele on dyslipidemia had multiplicative interactions (P = 0.016) and additive interactions (RERI = 0.403, 95% CI [-2.708 to 3.514]; AP = 0.376, 95% CI [-2.041, 2.793]). Meanwhile, HbA1c levels in rs3765467 A allele carriers (GA + AA) were found to be significantly lower than those in patients with GG genotype (P = 0.006). CONCLUSION: The rs3765467 (G/A) variant is associated with the incidence of dyslipidemia, and G allele may be a risk factor for dyslipidemia.

Effectiveness of a helmet promotion campaign, China.

Objective: To evaluate the effectiveness of a 2020 nationwide helmet promotion campaign, in terms of helmet wearing and correct helmet wearing, aimed at electric bike riders and motorcyclists in China. Methods: We obtained 192 hours of film of traffic before (2019) and after (2021) implementation of the campaign at eight road intersections in Changsha, recording cyclist (traditional and electric) and motorcyclist helmet-wearing behaviour during both weekdays and the weekend, and peak and off-peak traffic. We extracted data on rider characteristics and helmet-wearing behaviour. We applied a logistic regression to obtain estimates of helmet wearing and correct helmet wearing, and calculated odds ratios adjusted for rider variables. Findings: We filmed 11 525 cyclists and motorcyclists, 5256 (45.6%) before and 6269 (54.4%) after the campaign. We estimated a substantial increase in the overall percentage of helmet wearing from 8.8% (95% confidence interval, CI: 8.0-9.6) to 62.0% (95% CI: 60.8-63.2). After controlling for covariates, we noted that helmet wearing increased in all groups. However, we observed a decrease in the overall percentage of correct helmet wearing from 91.9% (95% CI: 89.4-94.3) to 83.5% (95% CI: 82.3-84.7). Post-campaign, we estimated the highest percentage of helmet wearing for delivery riders (88.8%) and lowest for traditional cyclists (3.8%); we estimated the lowest percentage of correct helmet wearing for three-wheeled motorcyclists (58.8%). Conclusion: To increase helmet wearing and correct helmet wearing, we recommend amending the campaign to include traditional cyclists as well as education and legislation on the correct fastening of helmet chinstraps.

Assessing the effectiveness of an app-based child unintentional injury prevention intervention for caregivers of rural Chinese preschoolers: protocol for a cluster randomized controlled trial.

BACKGROUND: Compared to urban children, children living in rural areas of most countries, including China, are at higher risk of suffering unintentional injuries. Most proven injury prevention interventions, however, are rarely implemented in rural China due to lack of resources. Mobile health interventions are low-cost and easy-to-implement, facilitating implementing injury prevention in resource-limited areas (e.g., rural areas). This study is designed and implemented to examine the effectiveness of an app-based intervention for unintentional injury prevention among rural preschoolers in China. METHODS: A single-blind, 18-month, parallel-group cluster randomized controlled trial with 1:1 allocation ratio will be implemented in 2 rural areas of China (Yang County, Shaanxi Province, and Shicheng County, Jiangxi Province). In total, at least 3508 rural caregivers of preschoolers aged 3-6 years old who own a smartphone will be recruited from 24 preschools. Clusters will be randomized at the preschool level and allocated to the control group (receiving routine school-based education plus app-based parenting education excluding unintentional injury prevention) or the intervention group (receiving routine school-based education plus app-based parenting education including unintentional injury prevention). External support strategies will be adopted by local partners to minimize user fatigue, non-compliance, and attrition. Data collection will be conducted at baseline and then every 3 months during the 18-month follow-up time period. Intention-to-treat data analysis will be implemented. Missing values will be imputed by using the Expectation Maximization algorithm. Generalized estimating equation will test the overall effectiveness of the app-based intervention. A per-protocol sensitivity analysis will be conducted to test the robustness of results. Subgroup analyses will follow the strategies for primary analyses. The primary outcome measure is the incidence rate of unintentional injury among preschoolers during the study period. Secondary outcome measures comprise longitudinal changes in caregiver's attitudes, caregiver-reported supervision behaviors, and caregiver-assessed home environment safety surrounding child unintentional injury prevention in the last week using a standardized audit instrument. DISCUSSION: The app-based intervention is expected to be feasible and effective over the 18-month intervention period. If the app is demonstrated effective as hypothesized, we will initiate processes to generalize and popularize it broadly to rural child caregivers across China. TRIAL REGISTRATION: ChiCTR2000037606 , registered on August 29, 2020.