Clinical Pharmacology & Therapeutics最新文献

Proton pump inhibitors (PPIs), commonly prescribed for gastrointestinal disorders, have been investigated for their association with the risk of dementia. We aimed to assess the association between PPI use and dementia risk in older adults and examine the influence of methodological choices on this association. We conducted a meta-analysis of longitudinal observational studies, including subgroup analyses to address time-related biases and comparator selection. Relevant studies were systematically searched in the MEDLINE, Embase, and CENTRAL databases from their inception to January 25, 2026. Twenty-three studies of older adults without dementia at baseline, reporting adjusted estimates for PPI users versus a comparator group, met the inclusion criteria. The pooled hazard ratio (HR) indicated a modest association between PPI use and dementia (HR = 1.18, 95% confidence interval [CI] 1.02-1.37). Dementia risk did not differ significantly between PPI users and users of histamine-2 receptor antagonists (H2RAs) (HR = 1.04, 95% CI 0.89-1.20). In a post hoc analysis, H2RA use itself was associated with dementia (HR = 1.44, 95% CI 1.07-1.93), whereas excluding H2RA-treated patients strengthened the PPI estimate (HR = 1.75, 95% CI 1.38-2.22). Estimates also differed according to how time-related bias was handled: lag time, HR = 1.25, 95% CI 1.07-1.46; time-varying exposure, HR = 1.38, 95% CI 1.16-1.64. PPI use was modestly associated with incident dementia. However, the strength and specificity depended substantially on comparator selection and handling of time-related bias. Well-designed, long-term studies using active comparators are needed to clarify whether this effect is PPI-specific.

Biosimilar development for therapeutic proteins (TPs) with limited systemic exposure presents distinct challenges, as the new paradigm based on comparative analytical assessments plus pharmacokinetic similarity without a comparative efficacy study (CES) is inapplicable. Of 19 TPs with limited systemic exposure, 15 are well-characterized, of which 12 have at least one CES-feasible indication. The remaining 3 may require alternative strategies, including pharmacodynamic (PD) biomarker approaches or optimized CES designs, underscoring the need for proactive regulatory engagement.

Hyponatremia poses risks in type 2 diabetes, yet comparative electrolyte safety across glucose-lowering therapies remains unclear. We evaluated the risk of incident hyponatremia associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 (DPP-4) inhibitors in real-world practice. Using electronic health records from 155 healthcare organizations in the TriNetX Global Collaborative Network, we conducted multicenter active-comparator, new-user target trial emulations with 1:1 propensity score matching. For each pairwise comparison, adults with type 2 diabetes initiating either drug class, with no record of either class during the preceding 365 days, were included. The primary outcome was incident hyponatremia (ICD-10-CM E87.1 or serum sodium ≤ 135 mmol/L); sensitivity outcomes included diagnosis-only, laboratory-only, and stricter laboratory thresholds. Among more than 300,000 matched pairs per comparison, SGLT2 inhibitors and GLP-1 RAs were each associated with a 15% lower hazard of hyponatremia than DPP-4 inhibitors (hazard ratio [HR], 0.850; 95% confidence interval [CI], 0.842-0.858 and HR, 0.847; 95% CI: 0.838-0.856). The lower risk persisted at stricter sodium thresholds and across clinically relevant subgroups, including patients with heart failure, chronic kidney disease, or high-risk medications use. SGLT2 inhibitors and GLP-1 RAs were broadly comparable (HR, 0.962; 95% CI: 0.952-0.971). Positive and negative control outcomes were consistent with expectations. Overall, SGLT2 inhibitors and GLP-1 RAs were associated with a lower risk of incident hyponatremia than DPP-4 inhibitors. These real-world findings provide reassurance regarding the electrolyte safety of SGLT2 inhibitors and GLP-1 RAs, complementing their established cardiorenal benefits.

Clinical pharmacology and pharmacometrics teams are now being encouraged to implement the ICH M15 framework in drug development to support model-informed decisions in regulatory submissions. Although model performance is an important component of model evaluation, regulatory confidence also depends on the intended context of use (CoU) and the supporting level of evidence. This is particularly relevant for physiologically based pharmacokinetic (PBPK) modeling, where increasing regulatory application has strengthened the need for structured approaches to evaluate predictive performance, extrapolation, uncertainty, and model applicability. The Simcyp Simulator (V19R1) was recently qualified by the EMA for prediction of CYP-mediated drug-drug interactions (DDIs) involving six enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5), competitive inhibition, and mechanism-based inhibition for both victim and perpetrator drugs across three CoUs. Qualification data demonstrated consistent predictive performance across the three CoUs, with average fold errors close to unity, absolute average fold errors ranging from 1.23 to 1.25, and 98.8% of 246 predictions falling within 2-fold of observed values. The opinion predates ICH M15; however, it does not provide either a mapping to its credibility concepts or an operational basis for extending platform-level evidence to a specific investigational drug. We address this gap with an explicit mapping of the qualification opinion onto ICH M15 credibility concepts and an integrated approach linking qualification evidence, drug-specific validation, predictive performance, uncertainty characterization, and prospective application, illustrating how confidence in PBPK-supported regulatory decisions can be established within an ICH M15-aligned framework.

Model-informed drug development (MIDD) and model-informed precision dosing (MIPD) increasingly guide drug development, regulatory decision-making, and individualized therapy but rely on robust data. Current models inadequately represent children with medical complexity (CMC), whose unique physiology, comorbidities, and polypharmacy contribute to substantial variability in drug exposure and response. We propose a framework using genotype-stratified trials to characterize pharmacogenetic sources of variability, informing MIDD and MPID models while helping identify additional determinants of therapeutic response in CMC.

Model-informed drug development increasingly depends on collaboration among clinical pharmacology, statistics, pharmacometrics, and quantitative systems pharmacology. Yet functional silos, distinct leadership structures, and divergent goals can reduce collaboration to late, parallel deliverables that constrain decision architecture. This Perspective defines a shared decision system as an operating model in which quantitative and clinical disciplines jointly define the question, context of use, evidentiary role, uncertainty standards, and accountability for model-informed evidence.

Pregnant and breastfeeding individuals are routinely excluded from clinical drug development, creating persistent evidence gaps in pharmacology, safety, and dosing. Despite mandatory contraception and pregnancy testing, unintended pregnancies occur, particularly during the development of central nervous system (CNS) medicines used by women of reproductive age. Once exposure to an investigational medicinal product (IMP) has occurred, these pregnancies may provide valuable prospective human data; however, treatment or trial participation is often discontinued and follow-up may be incomplete. This study assessed how unintended pregnancies and breastfeeding data were reported, managed, and evaluated in clinical trials supporting marketing authorization applications (MAAs) for CNS products. We reviewed 35 MAAs for centrally authorized CNS products submitted to the European Medicines Agency between 2012 and 2022. Pregnancy frequency, IMP exposure, pregnancy outcomes, breastfeeding data and regulatory comments were extracted from MAA dossiers, Day 120 Lists of Questions and Summaries of Product Characteristics. Overall, 451 pregnancies were identified, including 343 with IMP exposure. Of these, 108 occurred in pivotal phase 3 trials, resulting in 39 live births, 23 elective terminations, 17 spontaneous pregnancy losses, and 29 unknown or ongoing outcomes. Regulators raised 19 pregnancy-related and six breastfeeding-related concerns. Only one dossier included a dedicated human lactation study. Pregnancy reporting varied substantially in location, format and case-level detail, while 27% of pivotal IMP-exposed pregnancies had unknown or ongoing outcomes at assessment. More structured reporting and follow-up, including relevant exposure and pharmacokinetic data where feasible, could strengthen clinical pharmacology and regulatory evidence and support more informative product information.

The placenta serves a critical role in nutrient uptake and waste elimination for the developing fetus. The placenta is also responsible for the uptake and/or exchange of xenobiotics, including medications, between the maternal and fetal bloodstreams. An estimated 40-80% of women take medications or drugs during pregnancy. Very little is understood about fetal drug and nutrient exposure during pregnancy and how it may change over the course of fetal development. This study aimed to characterize the abundance of transport proteins in placental tissue, which are important in modulating fetal nutrient and drug exposure, over the duration of pregnancy. Using a mass spectrometry-based global proteomic approach, the relative abundance of proteins in placental tissue samples was profiled from first trimester, second trimester, and term placenta samples. Our analysis detected a total of 6331 proteins which included a total of 139 solute carrier and ATP-binding cassette transport proteins that were detected across the dataset, and 80 that were quantified in every sample. In general, membrane-associated proteins, including solute carrier and ATP-binding cassette transport proteins, were significantly enriched in placental tissue collected during early gestation compared to term placental tissue. Overall, this study presents a comprehensive profiling of membrane-associated proteomic changes during gestation and identifies significant gestational age associated abundance changes at the protein level in several transport protein families. These data provide critical information to support future studies into the understanding of fetal exposure to xenobiotics and nutrients circulating in the maternal bloodstream.

Almost half of individuals with hypertension fail to achieve recommended blood pressure (BP) goals. Pharmacogenetic gene-drug interactions may alter the efficacy of antihypertensive agents. We conducted a multicenter randomized controlled sub-study of participants (N = 1874) with hypertension and self-reported African ancestry to determine whether pharmacogenetic return of results (RoR) would improve systolic blood pressure (SBP) at 3 months. Participants were randomized to immediate pharmacogenetic RoR (intervention) or delayed RoR at trial completion (control). Clinical decision support conveyed recommendations for YEATS4-guided thiazide diuretic selection and NAT2-guided hydralazine dosing. Prespecified subgroup analyses included those with uncontrolled BP (baseline SBP ≥140 or DBP ≥90 mm Hg) and actionable genotypes. Immediate RoR did not improve SBP at 3 months in a broad population of hypertensive adults with controlled and uncontrolled SBP (covariate-adjusted change in SBP between groups: -0.3 ± 0.74 mm Hg, 95% CI: -1.8, 1.2). In participants with an actionable YEATS4 genotype (N = 867) predicting reduced thiazide efficacy, immediate RoR led to greater SBP reduction at 3 months (-2.46 mm Hg, 95% CI: -4.57 to -0.36). In participants with uncontrolled hypertension at baseline (N = 659), immediate RoR led to a greater reduction in SBP (-2.9 ± 0.74 mm Hg, 95% CI: -5.6, -0.3). Although no SBP reduction was observed in the whole cohort, participants with an actionable YEATS4 genotype or uncontrolled BP who received immediate RoR had a significantly greater SBP improvement than those with delayed RoR. Future studies of antihypertensive pharmacogenetics should recruit individuals with uncontrolled BP and actionable genotypes.

Lysosomes play a key role in the accumulation, catabolism, and transport of endogenous and exogenous metabolites and proteins and are involved in drug metabolism and prodrug activation. However, the protein abundance and interindividual variability of lysosomal drug-metabolizing enzymes and transporters (DMETs) remain underexplored. In this study, we performed a global proteomics analysis of the enriched human liver lysosomal fraction to characterize and annotate lysosomal proteins and compared these results with the proteomics data of hepatocyte homogenates and the liver microsomal fraction. We annotated and quantified 66 hydrolases and 41 membrane transporters in the lysosomal fractions. These included proteins involved in prodrug activation, transport, and metabolism or functioning as drug targets. After confirming the identity of lysosomal proteins, we investigated age-dependent changes in the abundance of these proteins in human hepatocytes (n = 58) across various age groups, ranging from neonatal (0–12 days) to adulthood (>18 years). We observed age-specific variations in the expression of key hydrolases (CTSA, CTSL, NAGLU, PLD3, and GALNS) and transporters (ATP6V1B2, ATP6V1C1, TMEM63A, and SLC39A14). Together, these findings highlight the lysosomal localization of proteins involved in drug disposition and their dynamic developmental changes, providing critical insights for refining physiologically based pharmacokinetic (PBPK) models to support precision dosing and improve therapeutic outcomes in pediatric populations.