Aim Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients. Methods A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models. Results In total, 217 patients were included. Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low‐weight bands. Simulations also showed significantly lower drug exposures in low‐weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration‐time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed‐dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low‐weight bands. Conclusion PK variability of first‐line anti‐TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.
Background Prospective studies correlating pharmacokinetic/pharmacodynamic (PK/PD) indices to clinical responses are urgently needed. This study aimed to find clinically relevant PK/PD thresholds that can be used for treatment optimization. Methods Pharmacokinetic sampling and minimum inhibitory concentration (MIC) measurements were performed for culture-confirmed tuberculosis patients. Classification and regression tree (CART) analysis was applied to obtain PK and/or PD thresholds for first-line drugs predictive of two-week/month culture conversion, treatment outcome determined at 6-8 months, acute kidney injury (AKI) and drug-induced liver injury (DILI). Least absolute shrinkage and selection operator (LASSO) logistic regression was used for model development and validation. Results Finally, 168 and 52 patients with tuberculosis were included in development and validation cohort for analysis, respectively. Area under concentration-time curve (AUC)/MIC below CART-derived thresholds for pyrazinamide of 8.42, pyrazinamide of 2.79 or rifampicin of 435.45 were the predominant predictors of two-week culture conversion, two-month culture conversion or treatment success, respectively. Isoniazid AUC above 21.78 mg·h/L or rifampicin AUC above 82.01 mg·h/L were predictive of DILI or AKI during TB treatment. The predictive performance of trained LASSO models in validation cohort was evaluated by receiver operating characteristic curves and ranged from 0.625 to 0.978. Conclusions PK/PD indices and drug exposure of anti-TB drugs were associated with clinical outcome and adverse events. The effect of CART-derived thresholds for individualized dosing on treatment outcome should be studied in a randomized controlled trial.
BackgroundUnderstanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimize treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment.MethodsDrug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and classification and regression tree (CART) analysis was used to identify key predictors and their clinical targets among patients on WHO-recommended regimens.ResultsDrug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. Target attainment was highly variable ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had higher probability of two-month culture conversion (56.3% versus 28.6%, OR 2.91, 95% CI 1.42–5.94) and favourable outcome (88.8% versus 68.8%, OR 2.89, 95% CI 1.16–7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin AUC/MIC of 231 and linezolid AUC/MIC of 287 as best predictors for six-month culture conversion in patients receiving identical Group A-based regimen. These association were confirmed in multivariate analysis.ConclusionsOur findings indicated that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomized controlled study to improve the MDR-TB treatment outcome.
Background Several anti-D immunoglobulin strategies exist for preventing Rh hemolytic disease of the fetus and newborn. This study systematically assessed the clinical value of those therapeutic strategies. Methods The Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for eligible studies that evaluated the value of different anti-D immunoglobulin strategies in preventing maternal anti-D antibody sensitization. Combined odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The network meta-analysis was conducted using Stata 14.2 and WinBUGS 1.4.3 software. Results Twenty-four original studies involving 64860 patients were included. Among all therapeutic measures, injecting 300 μg anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/E) appeared to be the most effective measure for preventing maternal antibody sensitization (surface under the cumulative ranking curve [SUCRA] = 96.8%), while a single injection at 28 gestational weeks (SUCRA = 89.2%) was the second most effective. Administering no injection or a placebo (SUCRA = 0.0%) was the least effective intervention measure. Conclusion Among the therapeutic measures, antenatal 5/E appeared to be the best method for reducing the positive incidence of anti-D antibodies in the maternal serum; thus, it may be the most effective treatment for preventing fetal hemolytic disease.
Background: Previous researches have reported that tripartite motif-containing 44 (TRIM44) is related to the prognosis of multiple human tumors. This study was designed to systematically assess the prognostic value of TRIM44 in human malignancies and summarize its possible tumor-related mechanisms. Methods: The available databases were searched for eligible studies that evaluated the clinicopathological and prognostic roles of TRIM44 in patients with malignancies. The hazard ratios (HR) and odds ratios (OR) were combined to assess the predictive role of TRIM44 using Stata/SE 14.1 software. Results: A total of 1740 patients from thirteen original studies were finally included in this study. The results of the combined analysis showed that over-expression of TRIM44 protein was significantly correlated with shorter overall survival (OS) (HR = 1.94, 95% CI: 1.60-2.35) and worse disease-free survival (DFS) (HR = 2.13, 95% CI: 1.24-3.65) in cancer patients. Additionally, the combined ORs indicated that elevated expression level of TRIM44 protein was significantly associated with lymph node metastasis (OR = 2.69, 95% CI: 1.71-4.24), distant metastasis (OR = 10.35, 95% CI: 1.01-106.24), poor tumor differentiation (OR = 1.78, 95% CI: 1.03-3.09), increased depth of tumor invasion (OR = 2.72, 95% CI: 1.73-4.30), advanced clinical stage (OR = 2.75, 95% CI: 2.04-3.71), and recurrence (OR = 2.30, 95% CI: 1.34-3.95). Furthermore, analysis results using Gene Expression Profiling Interactive Analysis (GEPIA) showed that the expression level of TRIM44 mRNA was higher in most tumor tissues than in the corresponding normal tissues, and the relationship between TRIM44 mRNA level and prognosis in various malignant tumors also explored in GEPIA and OS analysis webservers. Conclusions: TRIM44 may serve as a valuable prognostic biomarker and a potential therapeutic target for patients with malignancies.
BackgroundThe impacts of acquired resistance to first-line drugs (FLDs) during turnaround time (TAT) for drug susceptibility testing (DST) are still unclear. Thus, we aimed to investigate the impacts of acquired resistance to FLDs during TAT for DST on tuberculosis (TB) standard treatment.MethodWe performed a prospective cohort study between 2013 and 2018 in China, including sputum culture-positive TB patients with a baseline DST result for a Mycobacterium tuberculosis (Mtb) isolate collected at TB diagnosis and a follow-up DST result for a Mtb isolate collected when baseline DST result became available. Mtb isolates with acquired drug resistance were identified by the comparison between baseline and follow-up DST. Treatment outcome were evaluated by sputum culture conversion and World Health Organization (WHO) treatment outcome definitions. ResultsIn total, 65 patients with Mtb isolates with acquired resistance to any FLDs and 130 patients with consistent drug susceptibility profile were included in the analysis. In a Cox proportional hazard regression analysis, acquired pyrazinamide-resistance (aHR 0.54, 95%CI: 0.36-0.81) and acquired isoniazid-resistance (aHR 0.50, 95%CI: 0.29-0.85) were associated with prolonged time to sputum culture conversion. Furthermore, independent risk factors of treatment failure included acquired INH-resistance (aOR 7.64, 95%CI: 2.39-16.08) and acquired PZA-resistance (aOR 5.71, 95%CI: 2.31-14.12).ConclusionThe association between acquisition of drug resistance and treatment outcome highlights the importance of shortening the turnaround time of DST.
Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage.Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11).Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008–0.25 mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3–50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9–139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5–64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125 mg/L).Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.
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