Deeper understanding of innovative trial designs is beneficial to clinical pharmacologists. This includes seamless designs in oncology. From the data in an appropriately designed trial, mechanistic modeling uses information that is rich in content for generating clinical pharmacology (CP) evidence. However, as more advanced statistical designs are proposed, it becomes less straightforward for clinical pharmacologists to identify pros and cons of these designs from their perspective. This review article focuses on seamless Phase I/II designs for dose optimization in oncology and provides practical CP consideration examples in evaluating modern designs. The practical considerations span from the alignment with translational dose predictions to traditional CP assessment (e.g., QTc, and intrinsic/extrinsic factors). A comprehensive table of 23 seamless designs classified by CP consideration criteria, including a selected narrative review was developed. Example features include design compatibility with the type of modality, endpoints beyond maximum tolerated dose, translationally predicted efficacious dose range, dose escalation scheme, regimens for special populations, flexibility of the go/no-go decision algorithm integrating pharmacokinetic/pharmacodynamic (PK/PD) relationships, and future CP strategies. To achieve the benefit of optimal trial data generated in seamless designs, one should ensure essential features to inform CP packages are included as part of the trial design in a cross-functional team setting. Proactively getting involved in choosing a trial design with its go/no-go decision framework would allow clinical pharmacologists to make a positive impact. Optimizing designs will contribute to successful decision-making based on the totality of evidence in alignment with Project Optimus.
Body surface area (BSA)-based 5-fluorouracil (5-FU) dosing remains the standard in colorectal cancer despite substantial interpatient pharmacokinetic variability, which may lead to underexposure, treatment failure, or severe toxicity. This systematic review and meta-analysis evaluated whether pharmacokinetically guided 5-FU dosing improves efficacy and safety compared with conventional BSA-based dosing. PubMed/MEDLINE, Embase, and Scopus databases were searched from inception to the final search date. The search identified 1,802 records: PubMed/MEDLINE, 47; Embase, 118; and Scopus, 1,637 records. Comparative randomized and non-randomized studies evaluating pharmacokinetically guided, area under the curve–guided, or therapeutic drug monitoring–based 5-FU dosing versus BSA-based dosing in colorectal cancer were included. Random-effects models were employed. The risk of bias was assessed using RoB 2 and ROBINS-I, and the certainty of evidence was evaluated using GRADE. Five studies comprising 809 unique patients were included. Across the primary severe-toxicity analysis, the pooled denominator was 1,338 reported observations, including 625 in the PK-guided 5-FU dosing arm and 713 in the BSA-based 5-FU dosing arm, because one study reported severe toxicity by treatment cycle rather than by patient. PK-guided dosing was associated with lower severe or grade ≥ 3 toxicity (RR 0.50, 95
The electrocardiogram (ECG) remains the foremost non-invasive tool for detecting adverse drug effects on cardiac electrophysiology, encompassing QT interval prolongation, torsades de pointes (TdP), atrioventricular (AV) block, and sodium-channel-mediated QRS widening. As polypharmacy becomes ubiquitous — particularly in ageing populations and oncology — clinicians require a structured understanding of drug-ECG interactions to mitigate sudden cardiac death risk. A systematic narrative review was conducted using PubMed, Embase, and the Cochrane Library covering January 2006 to April 2026. Priority was given to meta-analyses, systematic reviews, scientific statements, and guidelines addressing drug-induced ECG changes, QTc measurement methodology, TdP risk stratification, and ECG monitoring protocols. Reference lists of key papers were hand-searched. Seventy references meeting quality and relevance criteria are cited. Numerous drug classes — including antiarrhythmics, antibiotics, antipsychotics, antidepressants, antiemetics, and oncology agents — prolong the corrected QT interval primarily through blockade of the cardiac hERG/IKr potassium channel. Modifiable risk factors include hypokalaemia, hypomagnesaemia, bradycardia, and co-prescription of CYP3A4 inhibitors. Female sex, age ≥ 65 years, congenital long QT syndrome carriers, and cardiac failure patients are at disproportionate TdP risk. The validated Tisdale Risk Score enables pre-treatment stratification in hospitalised patients. Drug-specific ECG monitoring protocols with actionable thresholds are summarised. Drug-induced ECG changes are common, clinically consequential, and often preventable. Evidence-based monitoring protocols, correction of modifiable risk factors, and prompt recognition of ominous ECG patterns substantially reduce adverse outcomes. Prescriber education across all clinical settings is imperative.
Rifampicin is known to induce clindamycin metabolism via CYP3A4/5, but the magnitude of this interaction varies greatly from one patient to another. Because this metabolic induction results from rifampicin activation of the nuclear pregnane X receptor (PXR), the genetic polymorphisms of its NR1I2 gene and that of CYP3A4/5 might predict the risk of clindamycin underdosage when combined with rifampicin. We therefore conducted a study to determine the possible influence of NR1I2 and CYP3A4/5 gene polymorphisms on baseline and rifampicin-induced clindamycin clearance. Eighty-five patients were included and sequentially received clindamycin by continuous infusion alone and then combined with rifampicin. The clindamycin steady-state concentration (Css) was measured for each patient before and during combination therapy. Clindamycin clearance during the 2 phases was calculated as the infusion rate/Css ratio. Five single nucleotide polymorphisms (SNPs) in the NR1I2, CYP3A4*22 and CYP3A5*3 genes were investigated. Clindamycin clearances alone and with combined rifampicin were 11.29 ± 5.54 and 46.14 ± 60.13 L/h, respectively. The minimal target clindamycin Css of 3 mg/L was not achieved in 31 patients. None of the investigated SNPs had any observed impact. None of the investigated SNPs can be used to predict the risk of clindamycin underdosage when combined with rifampicin. Further research is warranted to advance our understanding of this issue.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used in the management of type 2 diabetes mellitus (T2DM) due to their survival benefits. However, these agents are associated with increases in hemoglobin (Hgb) and hematocrit (Hct), raising concern for secondary polycythemia or erythrocytosis and potential thrombotic risk. The clinical significance of these hematologic changes remains unclear. We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. PubMed, Scopus, and Embase were searched up to February 2026 for studies evaluating the effect of SGLT2 inhibitors on hematologic parameters in adults with T2DM. Patients with primary polycythemia, end-stage renal disease (ESRD), or heart failure were excluded. Primary outcomes were changes in Hgb and Hct. Secondary outcomes included the incidence of erythrocytosis/polycythemia and thrombotic events. A total of 10 studies met inclusion criteria, comprising randomized and observational studies, with follow-up ranging from 8 weeks to 24 months. SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, were consistently associated with increases in Hgb and Hct. Across three randomized controlled trials, SGLT2 inhibitors significantly increased hematocrit (3 studies, 171 patients, pooled mean difference + 2.29
Management of symptomatic non-obstructive hypertrophic cardiomyopathy (HCM) remains challenging, and evidence comparing pharmacological therapies is limited. While several randomized controlled trials (RCTs) have evaluated individual agents, direct comparisons across multiple therapies are lacking. This study aimed to compare the efficacy of available pharmacological treatments for non-obstructive HCM using network meta-analysis. This frequentist network meta-analysis was conducted following PRISMA-NMA guidelines. Randomized controlled trials evaluating pharmacological therapies in adult patients with non-obstructive HCM were identified through systematic searches of major databases. Continuous outcomes were analyzed using mean differences (MD) with 95
This study aimed to explore patients’ satisfaction, informational needs, and preferences for how information on ADRs should be delivered. A digital survey was distributed among patients with chronic conditions. Closed-ended responses were analyzed quantitatively, whereas open-text responses were thematically analyzed to identify common themes. Two conceptual frameworks were developed to illustrate patients’ informational needs and preferences. 1,879 respondents participated. 47.2
Pharmacotherapy is a core competence for physicians and students’ learning is guided by examinations. This study aimed to examine medication-related examination questions across clinical courses spanning four semesters within a Swedish medical programme. In total, 375 questions used in four examinations (spring 2025; University of Gothenburg) were categorised independently, followed by consensus discussions, into mutually exclusive groups. In the first step, it was determined whether a question was medication-related; if so, the second step involved categorising its content according to the WHO 6-Step Model, which structures the physician ‘s pharmacotherapeutic workflow from defining the patient’s problem (differential diagnosis) and the therapeutic goal, to selecting and prescribing appropriate medications, counselling, and planning for monitoring and follow-up. Ninety-four (25
Opioid-related adverse effects have prompted interest in opioid-sparing strategies in joint arthroplasty. This systematic review evaluates the safety and efficacy of perioperative nefopam, a non-opioid, non-NSAID analgesic, in patients undergoing hip and knee arthroplasty. Medline, Cochrane, Embase, and Scopus were searched from database inception to September 2025. For meta-analysis, continuous outcomes were pooled as mean differences (MD) with 95
In a recent retrospective cohort from Norwegian memory clinics, Kersten and colleagues reported that potentially inappropriate medications for people with cognitive disorders were associated with faster two-year progression of mild cognitive impairment and dementia. We note that this progression signal was confined to exposure measured at the end of follow-up, was absent at baseline, and did not survive multivariable adjustment, a pattern more consistent with reverse causation and confounding by indication than with a drug effect. We further suggest that a simple count of inappropriate medications be refined through burden-weighted and class-specific analyses. Anchoring exposure temporally, applying negative control outcomes or target-trial emulation, and pursuing pragmatic deprescribing trials would help separate genuine drug effects from the clinical trajectory that drives prescribing.
Perioperative pain management is a significant challenge when using conventional µ opioid agonists, which often require careful balancing of efficacy and safety. Oliceridine, a G-protein-biased µ-opioid receptor agonist, may provide comparable analgesia while offering a potentially improved safety profile. Randomized controlled trials (RCTs) comparing perioperative oliceridine and sufentanil in adult patients were systematically identified from PubMed, Scopus, Embase, Web of Science, and the Cochrane Library from inception to March 21, 2026. Primary outcomes included respiratory depression, hypotension, and postoperative nausea and vomiting (PONV). Secondary outcomes comprised Quality of Recovery-15 (QoR-15) scores at 24 h, recovery time, extubation time, rescue analgesic requirements, 48-hour pain scores at rest, dizziness, bradycardia, and hospital length of stay. Random-effects models were used to estimate risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Trial sequential analysis (TSA) evaluated the robustness of the evidence. Seven RCTs (n = 1,327 patients; 1,242 in quantitative synthesis) showed that oliceridine reduced respiratory depression (RR = 0.48, 95
To investigate the role of CYP2D6 and its pharmacogenetic variability in the association between anticholinergic burden and cognitive function in older adults. We conducted a cross-sectional analysis of 872 community-dwelling adults ≥ 65 years from the ActiFE-Ulm cohort. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Anticholinergic burden scores deriving from CYP2D6-metabolised drugs (ABS2D6) were calculated for all regularly scheduled medications. CYP2D6 metaboliser status was determined via genotyping and categorised as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM). The 25th, 50th, and 75th percentiles of the MMSE score distribution were studied using quantile regression to examine the association between ABS2D6 and cognition, including interaction and stratified analyses by metaboliser status. ABS2D6 was significantly associated with lower MMSE scores at the 50th and 75th percentiles in early models, but not after additional adjustment for age and sex. A consistent effect modification by IM status was observed at the 75th percentile, with IMs showing a significant negative association between ABS2D6 and MMSE in stratified analyses (β = -0.34 [95
Psilocybin-assisted interventions are moving from efficacy trials toward psychiatric implementation. Cardiovascular interpretation is central to this transition because trial participants are generally medically selected, receive standardized pharmaceutical-grade doses, and are monitored more intensively than many patients encountered in routine care. This review translates the cardiovascular evidence into a risk-stratified psychiatric decision framework. We conducted a structured narrative review of clinical trials, systematic reviews, meta-analyses, cardiovascular pharmacology, drug-interaction studies, product-standardization literature, and implementation guidance. Searches were updated through July 10, 2026. Evidence was selected purposively to address acute hemodynamics, corrected QT interval (QTc), 5-hydroxytryptamine receptor-mediated effects, valvular biology, repeated exposure, naturally derived product variability, and practical screening and monitoring. In supervised studies, pooled estimates indicate mean increases of approximately 19.0 mmHg in systolic blood pressure and 8.7 mmHg in diastolic blood pressure. The largest and most consistent group differences occur about 60–90 min after dosing and generally resolve within 4–6 h; heart-rate effects are smaller and less consistent. Serious acute cardiovascular events remain uncommon in selected participants. Risk interpretation changes with cardiovascular comorbidity, interacting medications, repeated exposure, and non-standardized mushroom products, whose active-alkaloid content can vary by more than an order of magnitude. Mean QTc effects at standard exposure are small. A 5-HT2B-mediated valvular concern remains biologically plausible under chronic exposure, but assay results and exposure-margin estimates are heterogeneous and clinical valvular injury has not been established. Current evidence supports monitored, intermittent administration of standardized psilocybin in carefully selected populations, not general cardiovascular reassurance across all products, exposure patterns, or psychiatric settings. Product identity, medication review, risk-stratified cardiovascular assessment, session monitoring, and explicit escalation pathways should be integrated into treatment planning.
The World Health Organization recommends cohort event monitoring with a 30-day follow-up period for vaccine safety surveillance in low- and middle-income countries (LMICs). However, in resource-limited settings, operational and logistical constraints necessitate evaluation of the efficiency and feasibility of this follow-up duration. We conducted an analysis of a prospective active surveillance study of 10,948 adults who received the Pfizer COVID-19 vaccine in Ethiopia (August 2021–June 2022), using immediate observation and telephone follow-up on days 2, 4, 7, 14, 21, and 30. Among 10,948 participants, 4,236 (38.7
This systematic review and meta-analysis aimed to summarize the incidence of sleepiness in patients who used newer-generation antihistamines. CINAHL Complete, Medline, Scopus, ScienceDirect, and Google Scholar were systematically searched from inception to July 2025. The pairwise meta-analysis of the sleepiness incidence was conducted using a binary random-effects model. The network meta-analysis was performed using a random-effects model in a frequentist framework. Heterogeneity was evaluated using the I2 statistic. One hundred and sixty-three studies were included in the systematic review and meta-analysis. We found that 1.3
Synaptic density is strongly correlated with cognitive function in many neurological disorders. All synapses contain synaptic vesicle glycoprotein 2 A (SV2A), making it a potential therapeutic target for neurodecline. ABBV-552, a high-affinity positive SV2A modulator, increases neurotransmitter release, improving synaptic efficiency. This Phase 1, open-label, mass balance study examined ABBV-552 safety, pharmacokinetics, metabolism, and elimination. Eight healthy males were orally administered 15 mg [14C]-ABBV-552. Safety was assessed via treatment-emergent adverse event (TEAE), vital sign, electrocardiogram, and laboratory value monitoring. Serial blood, urine, and fecal samples were collected pre-dose, Days 1–14, and daily until discharge. Sample radioactivity was measured with HPLC and metabolites characterized with mass spectrometry. Eight participants (30–49 years old) received 15 mg [14C]-ABBV-552 ( 100 µCi) and were included in analyses (3 prematurely withdrew [personal reasons]). All TEAEs were Grade 1 in severity; euphoria (25.0
