British journal of clinical pharmacology最新文献

Background: Evaluating a patient's medication list is critical to reduce prescribing errors (PEs), but is a labour- and time-intensive process. Identification of patients at risk of PEs could improve the allocation of scarce time and resources, but currently available prediction tools are not effective.

Objective: To investigate whether ward doctors can identify patients at risk of PEs.

Methods: This prospective matched case-control study was conducted on three clinical wards in an academic hospital. Otolaryngology and oncology ward doctors used clinical intuition to select patients requiring a clinical medication review (CMR) (cases). These patients were then matched 1:1 on age (±10 years) and number (±1) of prescriptions with patients not selected for CMRs on the internal medicine and upper gastrointestinal surgery ward (controls). A multidisciplinary in-hospital pharmacotherapeutic stewardship team assessed the prevalence of PEs.

Results: A total of 387 patients with 5191 prescriptions were included. Overall, 799 PEs affecting 279 patients (72.1%) were identified. Most PEs (58.8%) occurred during hospitalization. There were no significant differences in age, number of prescriptions, sex, renal function or documented allergies or intolerances between the cases and controls or between controls and other patients who did not receive a CMR. The incidence of PEs was higher in cases than in controls (97.5% vs 72.5%, odds ratio = 14.8, 95% confidence interval [CI] 1.8-121.1, P = .002)). The rate of PEs was three times higher in cases than in controls (incidence rate ratio = 3.0, 95% CI 2.3-4.0, P < .001).

Conclusions: Ward doctors can effectively identify patients with PEs, and thus at risk of medication-related harm, using clinical intuition.

Aims: The emergence of drug-resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug-induced liver injury (DILI) with the BPaL regimen compared to first-line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]).

Methods: A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared.

Results: We identified 1242 cases of BPaL-related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74-8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55-4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3-28) compared to the HRZE regimen (20 days, IQR 6-48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003).

Conclusions: Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment.

Aims: The British Pharmacological Society and UK Medical Schools Council Prescription Safety Assessment (BPS/MSC PSA) is an electronic platform developed for assessing the prescription skills of medical students. Our aim was to investigate the feasibility of the BPS/MSC PSA in addressing prescribing competencies among junior doctors in a hospital setting.

Methods: The Department of Clinical Pharmacology at Odense University Hospital established a Danish translated programme using the BPS/MSC PSA platform. We launched a formal 3-year programme in 2021, potentially assessing all first-year doctors at Odense University Hospital and Esbjerg Regional Hospital. Participation was followed by a survey.

Results: During the period of 2021 to 2023 n = 364 doctors were invited, from which n = 246 participated. The compliance rate increased from 38% in 2021 to 88% in 2023. The mean assessment score (points normalized to percentage) across n = 246 participants was 71%, and 94% achieved a score of at least 50%. A subset of participants responded to the survey, with the majority of those completing the questionnaire indicating that the purpose of the assessment was clear. The items related to difficulty and number of questions received comparable evaluations, and most respondents found the questions clinically relevant.

Conclusion: It is feasible to translate and implement the BPS/MSC PSA in a Danish hospital setting. The programme provides insight into the prescribing competencies of junior doctors and the participants are generally positive.

Aims: Linezolid is primarily used to treat of methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples.

Methods: Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations.

Results: Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R = .833, P < .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R = .885, P < .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0.

Conclusion: The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration.

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Safety, pharmacokinetics and antiviral activity of ainuovirine as 10-day monotherapy in treatment-naïve adults with HIV-1

Su Bin¹, Wu Hao¹, Wei Xia¹, Zhang Li², Yun Xinming² and Qin Hong²

¹Beijing Youan Hospital Affiliated to Capital Medical University; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Background: Ainuovirine (ANV) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This study aimed to evaluate the safety, pharmacokinetics and antiviral activity of short-term ANV monotherapy in antiretroviral treatment-naive adults with HIV-1.

Methods: A single-centre, open-label, dose-ranging study was conducted among 28 treatment-naive adults with HIV-1. Participants received ainuovirine monotherapy, at the dosage of 75, 150 or 300 mg, once daily, for 10 days.

Results: Baseline characteristics were similar across dose cohorts (75 mg, n = 8; 150 mg, n = 10; 300 mg, n = 10). Across all dose cohorts, all adverse events were rated as mild to moderate in severity. No serious adverse event was reported. ANV was readily absorbed, with the maximum concentration achieved at a median time of approximately 2–3 h after dosing. The ANV exposure (AUC and C_max) increased slightly greater than the dose proportionality after single dose (day 1). Plasma ANV concentration reached the steady state at day 10 of dosing. Saturated C_max,ss, AUC_max,ss, and C_min,ss were observed at 150 and 300 mg on day 10 after repeated dosing. The inhibitory quotient (IQ) was 69.6-fold (150 mg, C_min,ss = 153.0 ng/mL) for wild type (EC50 = 2.2 ng/mL), 10.0-fold for K103N mutant (EC50 = 15.3 ng/mL) and 6.9-fold for Y181C mutant (EC50 = 22.1 ng/mL), respectively. Mean changes in HIV RNA from baseline (log10 copies/mL [90%CI]) were −1.73 [−1.90, −1.57], −1.72 [−1.87, −1.57] and −1.66 [−1.80, −1.51], respectively, on day 11.

Conclusion: ANV demonstrated favourable safety and pharmacokinetics, and potent antiviral activity in treatment-naive adults with HIV-1. An once-daily dosing regimen of 150 mg was recommended for subsequent confirmatory efficacy trial.

Keywords: ainuovirine, anti-HIV treatment, viral kinetics

Aim: Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.

Methods: We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.

Results: Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (R_C:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher R_C:PBMC ratios of 42.4% and 60.7%, respectively.

Conclusion: Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.