British journal of clinical pharmacology最新文献

Aims: This study investigated the started sample size, completed sample size and drop-out rate of 10 252 published and unpublished phase III clinical trials registered on ClinicalTrials.gov over the past 20 years.

Methods: We conducted a comprehensive search on ClinicalTrials.gov for all phase III clinical trials with registered results before 26 May 2023. We retrieved and downloaded 10 252, which covered a period of more than 20 years.

Results: Out of the 10 252 trials analysed, 889 (8.7%) were sponsored by the US National Institutes of Health/US Federal agencies (NIH/US Fed), 8429 (82.2%) were sponsored by industry. The overall median started sample size was 302. The overall median completed sample size was 228. The median completed sample sizes were 258 for industry-sponsored trials, and 194 for NIH/US Fed-sponsored trials. The median completed sample sizes were 321 for biological interventions and 223 for drug interventions. The overall median drop-out rate was 11%. Statistically significant differences were observed in sample sizes between industry-sponsored trials and NIH/US Fed-sponsored trials (P < 0.0001). Neither the started sample sizes nor the completed sample sizes have shown any change over the course of the past 20 years.

Conclusions: Our findings indicate that a majority of the analysed trials lack sufficient statistical power (80%) to detect small effect sizes, and approximately half of the trials did not have 80% power to detect medium effect sizes. Notably, trials funded by NIH/US Fed exhibit significantly smaller sample sizes compared to trials sponsored by industry. When conducting sample size calculations for clinical trials, it is crucial to consider the anticipated effect size, variability and drop-out rate.

Aims: Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.

Methods: The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were performed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses.

Results: Thirty-six children were enrolled [median age 4.8 (range 0.4-15) years and weight 15.6 (range 6.9-42.1) kg]. A two-compartment disposition model with first-order elimination and delayed absorption was developed. The bioavailability of dispersible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95-1.15). Simulations showed WHO-recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%-56% higher doses to reach adult reference exposures.

Conclusions: Dosing recommendations for children can be the same for the dispersible paediatric and standard non-dispersible adult moxifloxacin formulation. The current WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.

Aim: Area under the concentration-time curve (AUC)-guided dosing is recommended in vancomycin therapy. This study aims to determine the empirical dosing for achieving an AUC on the first day (AUC_f24h) and the optimal number of samplings for Bayesian estimation.

Methods: A multicentric prospective study was conducted across five hospitals. Critically ill patients were included, with rich sampling conducted on the first day and/or days 3-5 of therapy. Cumulative dose on the first day for the trapezoidal AUC_f24h > 400 μg·h/mL and the predictive performances of AUC and clearance in limited sampling were evaluated. The probability of adherence to AUC_f24h within 400-600 μg·h/mL in the guidelines-compliant or non-compliant doses were also evaluated.

Results: The study included 27 patients and 395 samplings were performed. The mean cumulative dose (standard deviation) on the first day was higher in the group with AUC_f24h > 400 μg·h/mL at 49.3 (4.5) mg/kg compared to the group with AUC_f24h < 400 μg·h/mL at 42.1 (6.8) mg/kg (P = 0.01) for patients with creatinine clearance > 90 mL/min, respectively. The biases and variations of Bayesian posterior AUC by using only a trough concentration were improved by using two-point concentrations at trough and peak. The probability of adherence to AUC_f24h was significantly higher in the guidelines-compliant group (66.7%) than in the non-compliant group (11.1%, P < .01).

Conclusion: This study suggested an empirical dosage of about 50 mg/kg on the first day of vancomycin therapy and the use of two-point sampling in Bayesian estimations to enhance accuracy.

Trial registration: Not applicable because this is a non-intervention study.

Aims: Oxcarbazepine (OXC) has been approved as monotherapy or adjunctive therapy for paediatric partial seizures. There are few reports on the pharmacokinetics (PK) of OXC in paediatric patients with renal impairment (RI), especially dosage studies of RI, which are rarely conducted on paediatric patients. This study aimed to predict the PK of OXC in children with RI and to provide recommendations for dose adjustment in this population.

Methods: Physiologically based pharmacokinetic (PBPK) models of the active metabolites of OXC were developed and verified, and their disposition was simulated in populations with or without RI.

Results: A fold error value of less than 2 was observed based on the simulated results from PBPK models for single- and multi-dose administration. Based on the predictions for paediatric patients with moderate, severe, and end-stage RI, the dose should be adjusted to 50, 40 and 25% of the normal dose, respectively, in children aged 2-5 years; and 50, 30 and 20%, respectively, in children aged 6-17 years.

Conclusions: The developed PBPK model is a valuable tool for predicting the OXC dosage in paediatric patients with RI.

Aims: The aim of this phase 1 trial was to assess the pharmacokinetics, safety and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment vs. those with normal renal function.

Methods: Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) not on dialysis were compared with group-matched control participants with eGFR ≥ 90 mL/min/1.73 m². Eligible participants received a single oral dose of 150 mg balcinrenone, and blood and urine samples were collected for analysis.

Results: The total apparent balcinrenone clearance was 50% lower in the severe renal impairment group, resulting in an approximately two-fold higher area under the curve (AUC) and a 1.4-fold higher maximum observed plasma concentration in the severe renal impairment group compared with the control group. The terminal half-life and plasma protein binding were similar in both groups. Balcinrenone was safe and well tolerated in all participants. All reported adverse events were of mild-to-moderate severity and not considered related to balcinrenone.

Conclusions: Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on linear regression analysis of total apparent balcinrenone clearance vs. baseline eGFR, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m² compared with those with an eGFR of 60 mL/min/1.73 m². In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652]).

Introduction: Direct oral anticoagulants (DOACs) are used in patients with non-valvular atrial fibrillation (NVAF) to prevent complications such as embolic events. Poor adherence to DOACs increases the risk of these complications. This manuscript reviews the impact of once-daily (OD) vs twice-daily (BID) dosing regimens on adherence and persistence to the authorized DOACs (dabigatran, rivaroxaban, apixaban and edoxaban) in patients with NVAF, aiming to provide insights into guide clinical decision-making.

Methods: A systematic review was performed. First, a bibliographical search was carried out in PubMed, Scopus and the Cochrane Library. Articles that provided quantitative data comparing adherence and/or persistence associated with OD vs BID regimens of DOACs among patients receiving treatment for NVAF were included. Two analyses of adherence and persistence were conducted, one based on the overall outcomes and another, more restricted, to minimize the risk of overestimating results. Additionally, univariate analyses were conducted based on the number of follow-up days and the DOAC molecule.

Results: Thirty-nine studies, involving 976 494 patients, were analysed. The OD regimen demonstrated significantly higher adherence and persistence (P < .05) than the BID regimen in most outcomes. Adherence favoured OD in 53.1% of cases, while only 12.2% favoured BID. Similarly, persistence was higher with the OD regimen in 67.7% of cases compared to 14.9% for the BID regimen. These results remained consistent over time; nevertheless, variations were observed depending on the specific DOAC molecules.

Conclusion: Adherence and persistence of treatment with DOACs in patients with NVAF were greater for the OD than for the BID regimen.

Aims: Phenoconversion, a genotype-phenotype mismatch, challenges a successful implementation of personalized medicine. The aim of this study was to detect and determine phenoconversion using the solanidine metabolites 3,4-seco-solanidine-3,4-dioic acid (SSDA) and 4-OH-solanidine as diet-derived cytochrome P450 2D6 (CYP2D6) biomarkers in a geriatric, multimorbid cohort with high levels of polypharmacy.

Methods: Blood samples and data of geriatric, multimedicated patients were collected during physician counsel (CT: NCT05247814). Solanidine and its metabolites were determined via liquid chromatography/tandem mass spectrometry and used for CYP2D6 phenotyping. CYP2D6 genotyping was performed and activity scores (AS) were assigned. Complete medication intake was assessed. A shift of the AS predicted via genotyping as measured by phenotyping was calculated.

Results: Solanidine and its metabolites were measured in 88 patients with complete documentation of drug use. Patients had a median age of 83 years (interquartile range [IQR] 77-87) and the majority (70.5%, n = 62) were female. Patients took a median of 15 (IQR 12-17) medications. The SSDA/solanidine metabolic ratio correlated significantly with the genotyping-derived AS (P < .001) and clearly detected poor metabolizers. In the model adjusted for age, sex, Charlson Comorbidity Index and estimated glomerular filtration rate each additional CYP2D6 substrate/inhibitor significantly lowered the expected AS by 0.53 (95% confidence interval 0.85-0.21) points in patients encoding functional CYP2D6 variants (R² = 0.242).

Conclusions: Phenotyping of CYP2D6 activity by measurement of diet-derived biomarkers elucidates phenoconversion in geriatric patients. These results might serve as a prerequisite for the validation and establishment of a bedside method to measure CYP2D6 activity in multimorbid patients for successful application of personalized drug prescribing.