European Journal of Clinical Pharmacology最新文献

Objectives: This study aimed to quantitatively evaluate the efficacy and safety of first-line systemic therapies for treating advanced hepatocellular carcinoma (aHCC).

Methods: The study included clinical trials of first-line systemic therapies for aHCC since the approval of sorafenib in 2007. Hazard function models were used to describe changes in overall survival (OS) and progression-free survival (PFS) over time. Monte Carlo simulation was used to compare OS and PFS for different treatments, including sorafenib, antiangiogenic therapies (AATs) (except sorafenib), immune checkpoint inhibitor (ICI) monotherapy, AAT + targeted therapy, AAT + chemotherapy, AAT + ICIs, and ICIs + ICIs. Furthermore, the objective response rate (ORR) and incidence of grade ≥ 3 adverse events were analyzed.

Results: Fifty studies comprising 12,918 participants were included. AAT + ICIs demonstrated a significant benefit in median OS (mOS), median PFS (mPFS), and ORR (20.5 [95% CI 17.5-24] months, 7.5 [95% CI 6.5-8.8] months, and 24% [95% CI 17%-30%], respectively). ICIs + ICIs and ICI monotherapy ranked second and third, respectively with an mOS of 20 (95% CI 18.5-21.5) months and 14.5 (95% CI 13.5-16) months, respectively. The OS, PFS, and ORR of patients treated with AAT, AAT + targeted therapy, and AAT + chemotherapy were similar to those of patients treated with sorafenib. A higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage C had a shorter OS. OS was associated with publication year, and PFS was associated with the proportion of patients with BCLC stage C. The incidence of grade ≥ 3 adverse events in the ICIs and ICIs + ICIs treatment groups was low.

Conclusions: The study results provide valuable information from which to base rational clinical drug use and serves as a reliable external control for evaluating new treatments for aHCC.

Background and objectives: Bedaquiline (BDQ) plays a critical role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, the large pharmacokinetic (PK) variability of BDQ presents a significant challenge in its clinical use. This study aimed to summarize the population PK characteristics of BDQ and to identify significant covariates affecting the PK variation of BDQ.

Methods: The PubMed and Web of Science databases were systematically searched from their inception to October 1, 2023. Population pharmacokinetics (PPK) studies on BDQ were searched and identified in this review. The PK characteristics of included studies and the significant covariates were systematically summarized.

Results: Eight studies conducted in adults and one in children and adolescents were included in this review. A three disposition compartments with dynamic absorption transport chamber model was the commonly used structural model for BDQ. Body weight, race, albumin, and concomitant medication were significant covariates affecting BDQ PK variation. With the increase of weight and albumin levels, the clearance (CL) of BDQ was gradually increased. The average CL value per body weight in children was 1.49-fold higher than that in adults. Black race patients had an 84% higher CL than other populations. Moreover, combined with rifampicin and rifapentine, BDQ had 378% and 296% higher clearance rates, respectively.

Conclusions: Body weight, race, albumin level, and concomitant medication may be important factors affecting patients' exposure differences. Further PPK studies of BDQ are needed to facilitate optimal dosing regimens.

Background: The potential nephrotoxicity of cyclosporine A (CsA) has been a problem for treating graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the relationship between CsA blood concentration and acute kidney injury (AKI) in pediatric patients after allo-HSCT remains unclear.

Methods: We performed a retrospective study including pediatric patients who received allo-HSCT in West China Second Hospital of Sichuan University from 2000 to 2022 and collected their clinical data. Included patients' CsA blood concentration were divided into three cohorts according to the guideline. Multivariate logistic regression was used to estimate the relationship between AKI and CsA blood concentration and other factors. And the maximum cut-off value for the safe blood concentration range of CsA was obtained by the receiver operating characteristic (ROC) curve.

Results: Seventy-nine patients (average age 6.75 ± 4.25) were included. The incidence of kidney injury for three CsA blood concentration cohorts (< 200 ng/ml, 200-300 ng/ml, > 300 ng/ml) were 21.30%, 23.50%, and 66.70%, respectively. A multivariate logistic regression identified CsA blood concentration (> 300 ng/ml) and infection were risk factors for AKI (OR _<200 ng/ml: 0.115, 95% CI: 0.029-0.458; OR _{200-300 ng/ml}: 0.184, 95% CI: 0.036-0.929; OR _infection: 5.006, 95% CI: 1.491-16.810). Meanwhile, the maximum cut-off value for the safe blood concentration range of CsA is 276.85 ng/ml with an AUC value of 0.684 (P = 0.010).

Conclusion: In conclusion, clinical treatment for the pediatric patients after allo-HSCT may be considered to control the blood concentration of CsA in 200-276.85 ng/ml and closely monitoring patients who have infections.

Background: Contrast-induced nephropathy (CIN) is an adverse renal event that occurs following the administration of contrast media for diagnostic procedures or therapeutic angiographic intervention. Nevertheless, there is currently no efficacious and safe agents for the treatment of CIN, except for hydration. We aimed to conduct a meta-analysis to verify the potential nephroprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in the prevention of CIN.

Methods: The PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) databases were searched from their respective inception dates up until 26 August 2024. The "Meta" package of R and Stata software was used for data analysis.

Results: A total of 12 studies were included in the analysis, comprising 11 single-center retrospective studies and one prospective cohort study. Our meta-analysis determined that SGLT2is significantly decrease CIN (odds ratio (OR) 0.39, 95% confidence interval (CI) (0.31, 0.48), P < 0.0001, I² = 0%) and mortality (OR 0.45, 95% CI (0.26, 0.77), P = 0.0039, I² = 48%). No notable discrepancy was discerned in continuous renal replacement therapy (CRRT) (OR 0.53, 95% CI (0.15, 1.91), I² = 0%) or contrast volume (MD - 9.68, 95% CI (- 19.38, 0.03), I² = 71%).

Conclusion: The present study demonstrated that SGLT2is markedly reduce the incidence of contrast-induced nephropathy in diabetic patients. It is recommended that future large-scale randomized controlled trials (RCTs) are required to confirm these findings and to elucidate further the outcomes in patients without diabetes.

Purpose: Voriconazole (VRC) is recommended for the prevention and treatment of invasive fungal infections in children undergoing hematopoietic stem cell transplantation (HSCT). It demonstrates nonlinear pharmacokinetics (PK) and exhibits substantial inter- and intraindividual variability. Phenytoin sodium (PHT) and methylprednisolone (MP) are commonly used in the early stages of HSCT to prevent epilepsy and graft-versus-host disease. Drug-drug interactions between VRC and these medications represent a significant concern in HSCT recipients. This study aims to investigate the effects of coadministration with PHT, MP, and other covariates on VRC metabolism in children with thalassemia (TM) undergoing allogeneic HSCT (Allo-HSCT) using population pharmacokinetics (PPK) and to recommend the optimal dosage regimen for this unique group.

Methods: A total of 237 samples from 57 children with TM undergoing Allo-HSCT were collected. Non-linear mixed effects modeling and Monte Carlo simulation (MCS) were applied for PPK analysis and for optimizing VRC dosing, respectively.

Results: The VRC data were characterized by a two-compartment model with linear elimination and first-order absorption. All parameters were incorporated in allometric scaling form, with PHT and MP significantly influencing VRC clearance. The MCS revealed a negative correlation between the children's body weight (ranging from 10 to 40 kg) and the required dose. When PHT was co-administered, approximately three times the regular dose of VRC was required. In contrast, when MP was administered together, the dose needed to be increased by 12.5-50%.

Conclusion: The proposed regimen improved the probability of target attainment for VRC and may serve as a reference for the individualized administration of VRC in clinical practice.

Objectives: This study aimed to characterize non-commercial Spanish COVID-19 trials and to determine the availability of results. Differences in outcomes according to the interventions assessed (medicines, non-medicines) will also be determined.

Methods: This systematic review was conducted in March 2024 by searching non-commercial Spanish COVID-19 trials on four registers (EUCTR, Clinical.

Trials: gov, ISRCTN, DRKS) and the WHO ICTRP. Phase-1 medicines trials were excluded. Several variables were retrieved from registers. Publication of main trial results were searched on PubMed, Cochrane COVID-19 Study Register, and Google Scholar. Journals' impact factor and articles' citations on Google Scholar were also registered. Results from medicines and non-medicines trials extracted from registers and articles were compared.

Results: A total of 170 trials (57.1% medicines trials) were identified. These 170 trials were randomized (87.1%), masked (41.8%), or multicenter (39.4%); a total of 15,555 participants were enrolled, mostly in small trials (median, n = 88). Only 8.8% (15/170) of trials posted results on the registers; only 47.6% (81/170) of trials had either published results or posted them on registers. Publications accounted for 92.6% (75/81) of these. Articles were published in 56 different journals, had a median impact factor of 4.4 and a median of 10 citations. Most (58.7%, 44/75) described negative results. There were statistically significant differences (p < 0.001) between medicines and non-medicines trials on timely registration and on being multicenter. This was also the case among published trials with respect to negative results of the primary endpoint.

Conclusion: Although most trials were randomized, a minority were multicenter, large, or masked. Trial results should be posted on the registers to make them accessible to everyone.

Purpose: Tranexamic acid (TXA) is widely used as an antifibrinolytic drug. However, studies to determine the optimal blood concentration of TXA have produced inconsistent results. During cardiac surgery, cardiopulmonary bypass (CPB) has serious effects on drug distribution, elimination, and plasma concentration. Therefore, we aimed to establish a population pharmacokinetics model of TXA in patients undergoing cardiac surgery with CPB that considers renal function as a covariate, thereby facilitating personalized treatment.

Methods: In total, 453 TXA plasma samples were prospectively collected from 77 patients who underwent cardiac surgery with CPB. Plasma concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model of TXA was analyzed using nonlinear mixed-effects modeling.

Results: The two-compartment-based model with combined errors was determined as the best. The final model included the effect of bodyweight and CL_cr may be summarized as V₁ (L) = 12.77 × (bodyweight / 61.4)^0.911, V₂ (L) = 6.857, CL₁ (L/h) = 3.263 × [CL_cr (L/h) / 61.0]^0.752, CL₂ (L/h) = 2.859.

Conclusion: Patients who undergo cardiac surgery with CPB may require an adjusted dose of TXA tailored to CPB due to lower CL₁ and increased V₁. Our TXA population pharmacokinetic model may be useful for developing individualized dosing designs for TXA in patients who undergo cardiac surgery with CPB.

Purpose: Opioids are frequently used to treat pain in neonatal intensive care units (NICU) with fentanyl, morphine and sufentanil being mainly used agents. Equianalgesic potency between opioids is not clearly described in the neonatal population. The aim of this study was to compare theoretical and actual equipotent conversion ratios between morphine, sufentanil and fentanyl based on prescriptions.

Methods: In this observational, multicentric, pharmacoepidemiologic study, prescriptions' data (doses, duration of use, patients' characteristics) were collected and analyzed for all neonates hospitalized in one of the 30 Level III French NICUs using the same prescription software (Logipren®) and who received at least one prescription of morphine, sufentanil or fentanyl as continuous infusion during a 6-year period (2014-2020).

Results: Among 65,555 neonates, 8361 (12.8%) received a prescription of continuous opioid infusion in one of the 30 French NICUs: 5054 (60.4%) received sufentanil, 2413 (28.9%) morphine and 894 (10.7%) fentanyl. After conversion to equipotent morphine doses using theoretical conversions ratios of 50:1 for morphine/fentanyl ratio and 500:1 for morphine/sufentanil ratio, prescribed mean maintenance doses of fentanyl and sufentanil were two times and five times higher than morphine doses, respectively. In this cohort, potency conversion ratios between the different opioids were 20:1 for morphine/fentanyl ratio and 100:1 for morphine/sufentanil ratio, and 4:1 for fentanyl/sufentanil ratio (theoretical conversion ratio of 7: 1).

Conclusion: In a large cohort of neonates treated with continuous opioids in NICU, fentanyl and sufentanil doses used were significantly higher than morphine doses when using theoretical conversion ratios.

Objective: In part I, measure the EC50 of sufentanil in obese and non-obese parturients combined with 0.1% ropivacaine and compare the differences. Similarly, in part II, measure the EC50 of ropivacaine in obese and non-obese parturients combined with 0.5 µg/ml sufentanil and compare the differences.

Methods: This study comprises two parts, with an initial intention to enroll 120 full-term primiparous women who underwent vaginal delivery and sought epidural analgesia. Each part includes an obese group (OA group, Obese Adults, defined as prepartum BMI≥29 kg/m²) and a non-obese group (CON group, Control group, defined as 18.52), with 30 participants in each. Both parts, for both obese and non-obese women, utilized an initial concentration of 0.1% ropivacaine with 0.5 µg /ml sufentanil. The initial concentration of sufentanil is 0.5 µg/ml. When the NRS score is ≤3 within 30min after analgesia, it is considered effective analgesia, and the concentration of sufentanil in the next parturients decreases by 0.05 µg/ml. Otherwise, the concentration of sufentanil in the next parturient will increase by 0.05 µg/ml. The second part uses the same method to measure the EC50 of ropivacaine (increase or decrease by 0.01%) in the OA group and CON group combined with 0.5 µg/ml sufentanil, with 30 participants in each group. EC50 measurements were performed through up-and-down sequential allocation, with effective analgesia defined as an NRS score ≤3, 30 min post-analgesia.

Results: In part I, the EC50 of epidural sufentanil in the OA group was 0.090 µg/ml (95% CI, 0.061~0.115µg/ml), and in the CON group, it was 0.170µg/ml (95% CI, 0.117~0.219µg/ml). In part II, the EC50 of epidural ropivacaine in the OA group was 0.048% (95% CI, 0.041~0.053%), and in the CON group, it was 0.070% (95% CI, 0.064~0.075%). The secondary outcomes in both parts of the study showed no statistically significant differences.

Conclusion: Obese parturients exhibited significantly lower EC50 values for ropivacaine and sufentanil compared to non-obese parturients. Lower concentrations of both agents can be considered for labor analgesia in obese parturients.