Suzuki T, Nagai G, Mihara K
… +5 more, Tomori Y, Kagawa S, Nakamura A, Nemoto K, Kondo T
Int J Clin Pharmacol Ther
· 2026 May · PMID 41723744
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OBJECTIVES: Previous findings showing that lamotrigine co-administration decreases serum quetiapine concentrations were based solely on group comparisons using therapeutic drug monitoring databases. The present prospecti...OBJECTIVES: Previous findings showing that lamotrigine co-administration decreases serum quetiapine concentrations were based solely on group comparisons using therapeutic drug monitoring databases. The present prospective study examined the effects of lamotrigine co-administration on plasma quetiapine concentrations in Japanese patients with depression and in relation to polymorphisms of UGT1A2 and UGT2B7, enzymes responsible for lamotrigine metabolism. MATERIALS AND METHODS: 14 patients with depression were recruited in the study. They had been treated with immediate-release quetiapine 200, 400, or 700 mg/d. Lamotrigine was co-administered in all patients over a period of 8 weeks where the final doses of lamotrigine were 75 mg/d in 2 subjects taking valproate and 100 mg/d in 12 subjects not taking valproate. Blood samples were collected before and 2, 4, and 8 weeks after commencing lamotrigine co-administration. Quetiapine and lamotrigine concentrations in plasma were measured using LC/MS/MS. The genotypes of the 142T>G, -161C>T, and 372A>G polymorphisms were identified using real-time PCR analysis. RESULTS: The mean plasma concentration of quetiapine 8 weeks after lamotrigine treatment was significantly lower than that prior to the administration (p < 0.05). The mean percentage reduction in quetiapine concentration was significantly greater in subjects carrying the C/T and T/T genotypes when compared to those carrying the C/C genotype in respect to the -161C>T polymorphism (p < 0.05). CONCLUSION: The present study provides evidence that low-dose lamotrigine co-administration decreases plasma quetiapine concentrations in Japanese patients with depression and that the magnitude of this effect differs between genotypes of the -161C>T polymorphism.
Rosh B, Levi O, Stein N
… +2 more, Yahav A, Gronich N
Clin Pharmacol Ther
· 2026 Jun · PMID 41715957
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There is a paucity of data regarding the effects of prenatal disease-modifying therapies (DMTs) for multiple sclerosis (MS), on congenital anomalies in the offspring. Moreover, data on the association with neurodevelopme...There is a paucity of data regarding the effects of prenatal disease-modifying therapies (DMTs) for multiple sclerosis (MS), on congenital anomalies in the offspring. Moreover, data on the association with neurodevelopmental disorders are lacking. This is an historical cohort study, within the Israeli Clalit Health Services database (2005-2024) that included all children, born to mothers carrying a diagnosis of MS. Mothers' demographic and clinical characteristics were used to account for potential confounders. A marginal model used for the association between prenatal dispensed DMTs and neurodevelopmental disorders. A log-binomial regression model used to estimate relative risks (RR), 95% CI for the association between exposure and major congenital anomalies (MCAs). The cohort included 1374 children: 484 exposed prenatally to DMTs (237, 85, 56, 49, 25, 32 exposed to interferon-β, glatiramer, monoclonal antibodies, fumarates, sphingosine-1-phosphate receptor (S1PR) modulators, or a combination of therapies, respectively). In a mean follow-up of 7.5 years (maximum 19.8 years), prenatal exposure to DMTs was not associated with significant risk for neurodevelopmental disorders, in univariate and in multivariate models. Within 1252 children with 2 years of follow-up, 50 (3.9%) children were identified with MCAs. There was higher rate of MCAs among S1PR modulator-exposed children 2(8%). Due to the small group risk estimates for S1PR modulators had wide CIs, with RR = 2.0 (95% CI 0.51-8.1, P = 0.314); RR = 5.16 (95% CI 1.47-18.2, P = 0.011) in the univariate and sensitivity analysis, respectively. In conclusion, in the current cohort, prenatal exposure to DMTs was not associated with neurodevelopmental disorders. Exposure to S1PR modulators in pregnancy was associated with higher risk for congenital anomalies. Prospective larger studies are warranted.
Kattinakere Sreedhara S, Pillai HS, Desai RJ
… +11 more, Ngan K, Lai K, Lii J, Dutcher SK, Wang Y, Apata J, Tian F, Osaghae I, He J, Connolly JG, Wang SV
Claims-based analyses can suffer from residual and unmeasured confounding due to factors that are poorly captured in claims. Some of these factors may be measured in other data sources, such as in structured fields of el...Claims-based analyses can suffer from residual and unmeasured confounding due to factors that are poorly captured in claims. Some of these factors may be measured in other data sources, such as in structured fields of electronic health records (EHR), for example, laboratory test results, or in free-text physician notes. We conducted a proof-of-principle study to demonstrate a process for evaluating the potential risk of confounding-factors poorly captured in claims data but measurable in the EHR as part of drug safety surveillance activities. In future practical applications, this approach could be used along with other sensitivity analyses to evaluate potential residual confounding (e.g., E-values, negative controls). We used claims-EHR linked data from the Mass General Brigham site of the US Food and Drug Administration's (FDA) Sentinel Real World Evidence Data Enterprise. We extracted a cohort that was previously used in a prototypical Sentinel claims-based query that compared initiators of sacubitril-valsartan vs. angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the risk of angioedema. In this cohort, we used EHR data to characterize angioedema risk factors poorly captured in claims and observed that claims-based proxies balanced most risk factors that were measurable only in EHR data. While quantitative bias analysis methods can be used to adjust for residual confounding using external information on magnitude and direction of bias, this was deemed unnecessary for this example due to the observed balance achieved on risk factors for angioedema measured in the EHR. A robust linked EHR-claims data infrastructure is crucial for routine application of these methods to evaluate and mitigate residual confounding in drug safety surveillance studies.
Arshad U, Gaayeb L, Pertinez H
… +20 more, Rajoli RKR, Watkins M, Nimbolkar P, Perazzolo S, Pagi B, Wensing A, Khoo S, Boffito M, Holm R, Panos Z, Mahaka I, Venter F, Kottiri B, Crawford KW, Ho RJY, Clayden P, Domanico P, Struble K, Owen A, Flexner C
Clin Pharmacol Ther
· 2026 May · PMID 41704016
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The global HIV response aims for widespread availability of affordable, quality-assured long-acting antiretroviral (LA ARV) drugs to achieve sustained epidemic control, particularly in low- and middle-income countries. T...The global HIV response aims for widespread availability of affordable, quality-assured long-acting antiretroviral (LA ARV) drugs to achieve sustained epidemic control, particularly in low- and middle-income countries. This report summarizes key discussion points, findings, and outcomes from an international workshop on generic LA ARVs, held in Liverpool, United Kingdom, and co-organized by the Long-Acting/Extended-Release Antiretroviral Resource Program (LEAP) and the Centre of Excellence for Long-acting Therapeutics (CELT). The workshop brought together experts from across disciplines to evaluate the multifaceted challenges and opportunities for faster development and regulatory approval of affordable and accessible generic LA ARVs. Key topics included the application of novel pharmacokinetic end points to reduce study duration, the integration of community preferences into practice-based research in resource-limited settings, intellectual property considerations, formulation and manufacturing complexities that affect cost, scalability and implementation, and the growing role of model-integrated evidence in streamlining bioequivalence assessments. To reach the goal of timely and equitable global access to long-acting medicines, this workshop emphasized the need for strategic public-private engagement to promote data sharing, enhance regulatory efficiencies, and develop robust in vitro-in vivo correlation strategies that meet regulatory guidance for LAI products.
Kirchgesner J, Beaugerie L, Baumann C
… +26 more, Baert F, Rahier JF, Bergemalm D, Cañete F, Caron B, Cossignani M, Dias S, Farkas K, Girod P, Goren I, Holvoet T, Krasz S, Kumar A, Rimmer P, Sheridan J, Thut J, Uzzan M, Viazis N, Weimers P, Zagórowicz E, Buisson A, Avedano L, Rousseau H, Peyrin-Biroulet L, Sebastian S, I‐CARE Collaborator Group
Clin Pharmacol Ther
· 2026 Jun · PMID 41693257
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Investigator-initiated studies that include information collected by patients are rising, but limited data is available on patient and investigator experience in this setting. The I-CARE cohort included patients with inf...Investigator-initiated studies that include information collected by patients are rising, but limited data is available on patient and investigator experience in this setting. The I-CARE cohort included patients with inflammatory bowel disease (IBD) monthly collecting clinical information in 15 countries for up to 6 years. We describe patients and investigators' involvement in I-CARE and identify predictors of early withdrawal due to patient non-engagement. Patients' characteristics according to the number of electronic Patient-reported outcomes (ePRO) completed during follow-up were assessed. Predictors of early withdrawal due to patient non-engagement were identified using logistic regression. The coding of outcomes reported by patients and corrections by investigators on patients' ePROs were assessed. Among 12,846 patients included by 502 investigators, 79.3% and 77.3% filled more than one ePRO and at least one ePRO within 6 months before the study end date, respectively. All ePROs were completed in 72.8% and 56.4% of patients during year 1 and 3, respectively. Male gender, younger age (< 20), being unemployed or a student, and no previous history of abdominal surgery were associated with early withdrawal. Investigators corrected 52.5% of cancer or dysplasia reported by patients compared to 10% of serious infections. Investigators added or removed a treatment sequence in 19.6% of the 6708 patients treated with biologics. These results highlight the implication of patients in research and the importance of data validation by investigators alongside the challenge and potential of collecting medical data from patients. These findings can inform similar future initiatives in other diseases. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).
Jayachandran P, Ladumor MK, Vlasakakis G
… +11 more, Riselli A, Ilic KV, van Wijk RC, Elmeliegy M, Mukker JK, Sawant-Basak A, Long T, Dong J, Rayad N, Zhang T, DRO Network
Clin Pharmacol Ther
· 2026 May · PMID 41685721
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ASCPT has a mission to advance clinical pharmacology and translational sciences to reduce health disparities. The development, regulatory, and outcomes (DRO) network within ASCPT strives to advance pharmacoequity globall...ASCPT has a mission to advance clinical pharmacology and translational sciences to reduce health disparities. The development, regulatory, and outcomes (DRO) network within ASCPT strives to advance pharmacoequity globally. Pharmacoequity, coined by Utibe Essien (2021), is the principle that all individuals, regardless of race, ethnicity, geography, or socioeconomic status, should have access to high-quality and evidence-based therapies. This perspective spotlights the network's contributions toward this goal and identifies priority areas to build equitable health outcomes.
Clin Pharmacol Ther
· 2026 Jun · PMID 41685718
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Traditionally, clinical outcomes measuring how a patient feels, functions, or survives are preferred endpoints in clinical trials; however, some may take a long time to manifest in slowly developing diseases. Biomarkers,...Traditionally, clinical outcomes measuring how a patient feels, functions, or survives are preferred endpoints in clinical trials; however, some may take a long time to manifest in slowly developing diseases. Biomarkers, if properly validated, can serve as surrogate endpoints, acting as substitutes for clinical outcomes. This study investigated the extent and type of evidence demonstrating the correlation between biomarkers and clinical outcomes available in the literature before these biomarkers were first used as surrogate primary endpoints in pivotal studies supporting marketing authorization of cardiovascular and metabolic medicines in the European Union. Fourteen biomarkers newly used as surrogate endpoints between 2008 and 2023 were identified from European public assessment reports, and systematic literature searches were conducted for each of the identified biomarkers in PubMed and Embase to review existing evidence for the correlation between biomarker surrogates and clinical outcomes. We found that such correlation had often not been established in the literature prior to their use as a primary endpoint, as validation studies were identified for only four of the biomarkers. Of the 14 identified novel biomarker surrogates, all but one (93%) were used in trials for medicines with an orphan designation. Regulators seem to accept the use of surrogates in trials for rare diseases, despite limited validation, and consider the totality of evidence submitted to support authorization of the medicine. Presentation of complete and explicit justification for the choice and acceptability of biomarker surrogates in public documentation, such as European public assessment reports, should be encouraged.
Clin Pharmacol Ther
· 2026 May · PMID 41677365
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Regional differences in approved drug dosages and administration are shaped by complex factors, including clinical data, prior regulatory decisions, and region-specific considerations. This study investigated how such fa...Regional differences in approved drug dosages and administration are shaped by complex factors, including clinical data, prior regulatory decisions, and region-specific considerations. This study investigated how such factors are associated with variations in approved doses across the United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) in the context of recent global regulatory practices. We analyzed 111 new molecular entities approved in the United States and Japan from 2017 to 2023, incorporating EMA data where available. Dose concordance, defined as agreement between regions on the labeled approved dosing regimen for the same indication, was observed in 77% between PMDA and FDA and 84% between EMA and FDA, higher than rates reported in earlier studies. Nevertheless, significant regional differences remain. Qualitative analysis suggested that discordance in approved doses was associated with a small number of high-level factors, including differences in benefit-risk perspectives, approaches to dose determination, population-related considerations. Quantitative analysis indicated associations with trial design and submission timing. In a subset of 11 products in which FDA approval preceded approvals by other agencies and involved FDA-led dose modifications, patterns were observed that were consistent with potential interdependence in regulatory decision making, while sponsor-driven harmonization and shared evidence bases may also underlie these patterns. These findings suggest that early regulatory engagement and international coordination may support efficient dose selection, although attention must be paid to differing benefit-risk assessment considerations across regions.
India has strengthened its clinical research infrastructure and regulatory frameworks to support new drug development and early-phase clinical trials. However, historical concerns related to participant safety, ethics, a...India has strengthened its clinical research infrastructure and regulatory frameworks to support new drug development and early-phase clinical trials. However, historical concerns related to participant safety, ethics, and research capacity have limited the conduct of first-in-human (FIH) studies for products developed outside India. A multi-stakeholder panel comprising representatives from regulatory authorities, academia, industry, and funding agencies examined regulatory, ethical, infrastructural, and innovator perspectives relevant to conducting such FIH trials in India.
Richardson K, Kiptoo J, Mpora Odongkara B
… +2 more, Ojara FW, Waitt C
Clin Pharmacol Ther
· 2026 May · PMID 41670332
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This review evaluates the available pharmacokinetic data on the plasma-to-breastmilk transfer of first- and second-line T2DM drugs against available clinical guideline recommendations. A list of drug therapies for treati...This review evaluates the available pharmacokinetic data on the plasma-to-breastmilk transfer of first- and second-line T2DM drugs against available clinical guideline recommendations. A list of drug therapies for treating T2DM was generated from national and international clinical guidelines. A systematic search of research articles reporting human plasma and breastmilk drug concentrations was conducted in Scopus, PubMed, Google Scholar, and LactMed® in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies evaluating breastmilk drug transfer in T2DM, with fully accessible abstract and main text reported in English, were included. Study quality was evaluated using the ClinPK checklist. Authors evaluated clinical guideline recommendations on the use of T2DM drugs in lactation and the basis upon which such recommendations were made. Only 5 out of 20 drugs (metformin, glyburide, glipizide, tolbutamide, and semaglutide) have clinical data on plasma-to-breastmilk transfer. Metformin and tolbutamide were detectable in maternal plasma and breastmilk. Half (51.7%) of guideline recommendations provide explicit guidance. Only 4.4% of recommendations were based on clinical evidence. Over half (57.8%) of recommendations were accessible online, and most guideline recommendations (78%) were against the use of antiglycemic agents while breastfeeding. The scarce clinical evidence to guide T2DM drug therapy during breastfeeding available has several design and methodological limitations. Published recommendations remain largely inconsistent, thus perpetuating uncertainty in the use of T2DM drug therapies in lactation. Addressing knowledge gaps is critical in developing clinical consensus to optimize T2DM drug therapy among breastfeeding mothers.
Pignatti F, El-Galaly TC, Kaiser M
… +17 more, Porkka K, Doeswijk R, Mol P, Rivera DR, Lerro CC, Rohr UP, Verpillat P, Valachis A, Trapani D, Di Maio M, Latino N, Cordoba R, Cherny N, Koopman M, Martins-Branco D, Pentheroudakis G, Postmus D
Clin Pharmacol Ther
· 2026 Apr · PMID 41669939
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External comparator cohort (ECC) studies with real-world data (RWD) may provide more reliable estimates of treatment differences compared to single-arm trials (SAT), yet they face limitations such as selection bias and d...External comparator cohort (ECC) studies with real-world data (RWD) may provide more reliable estimates of treatment differences compared to single-arm trials (SAT), yet they face limitations such as selection bias and data heterogeneity. This study assessed the perceived strength of evidence of ECC studies compared to SAT and randomized controlled studies (RCT). The study included healthcare professionals (HCP) from the European Hematology Association (EHA), the European Society for Medical Oncology (ESMO), and assessors from international regulatory agencies (RA). A conjoint analysis evaluated strength of evidence ratings for establishing an effect on OS for different hypothetical scenarios, based on different designs, RWD quality, and observed OS improvement, for a new cancer treatment for advanced disease and no effective treatments. Participants from HCP organizations rated RWD studies favorably (advantages outweigh disadvantages) more frequently (47.6%; n = 103) compared to RA participants (12.9%; n = 116). Compared to a SAT, a high-quality RWD ECC study showing a 1.5-month and 3-month OS improvement had 2.7 (95% CI: 1.9-3.8) and 14.7 (95% CI: 10.0-21.5) times higher odds of receiving a higher strength of evidence rating, respectively. The OR for RCT v. SAT was 36.4 (95% CI: 24.0-55.2) and 358.4 (95% CI: 217.3-591.3), respectively. Strength of evidence ratings were associated with maximum acceptable risk of severe or symptomatic toxicity. In conclusion, when evaluating the OS of new therapies, ECC studies with RWD, especially when based on high-quality RWD or demonstrating a larger OS benefit, were rated as more convincing than SAT without a formal control.
Stancil SL, Fairley R, Bolds-Johnson L
… +2 more, Krebill H, Bierer BE
Clin Pharmacol Ther
· 2026 May · PMID 41668480
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Clinical trials drive therapeutic innovation but often underrepresent populations most affected by the disease. Despite efforts to include women, minorities, and children, participation still lags behind intent. Ensuring...Clinical trials drive therapeutic innovation but often underrepresent populations most affected by the disease. Despite efforts to include women, minorities, and children, participation still lags behind intent. Ensuring equitable representation is essential to maximize the impact of new therapies. This perspective offers actionable insights from a diverse panel-including patients, clinicians, researchers, and advocates-shared during the 2025 American Society for Clinical Pharmacology and Therapeutics Patient Forum.
Nardi Agmon I, Gurevitz C, Shochat T
… +8 more, Kushnir S, Witberg G, Levi A, Gilon D, Kornowski R, Thavendiranathan P, Abdel Qadir H, Iakobishvili Z
Clin Pharmacol Ther
· 2026 Jun · PMID 41665248
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) lower LDL cholesterol and may influence cancer through immunomodulatory pathways. However, their effect on human cancer incidence remains...Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) lower LDL cholesterol and may influence cancer through immunomodulatory pathways. However, their effect on human cancer incidence remains unknown. We conducted a retrospective, propensity score-matched study (Clalit Health Services, Israel, 2010-2023) comparing PCSK9 mAbs to ezetimibe. Adults prescribed PCSK9 mAbs for 6 months or more were matched 1:3 to ezetimibe-treated patients without prior cancer, applying a 1-year latency. The cohort included 9,876 patients (2,469 PCSK9 mAb; 7,407 ezetimibe; mean age 65). During a median 4.6-year follow-up, cancer occurred in 12% of PCSK9 mAb users and 11% of ezetimibe users (HR 1.09 [95% CI, 0.95-1.25]). In sex-stratified analysis, men on PCSK9 mAbs had a higher cancer incidence (12.5% vs. 10.3%, P = 0.03); no difference was observed in women. All-cause mortality was significantly lower in the PCSK9 mAb group (3% vs. 5%; HR 0.65 [95% CI, 0.54-0.80]). Post-cancer-diagnosis mortality did not differ. In this large cohort, PCSK9 mAb therapy appeared safe regarding overall cancer risk and was associated with a significant reduction in all-cause mortality; the slightly higher cancer incidence in men may likely be attributed to a higher prevalence of baseline risk factors.
In the field of rare diseases-where traditional clinical trials are often impractical-real-world data (RWD) have emerged as a scientifically valid alternative to support regulatory decision making. This study systematica...In the field of rare diseases-where traditional clinical trials are often impractical-real-world data (RWD) have emerged as a scientifically valid alternative to support regulatory decision making. This study systematically evaluates the utilization of RWD in orphan drug approvals by the FDA Center for Drug Evaluation and Research (CDER) over the past 5 years (2020-2024). We reviewed marketing applications for orphan drugs approved during this period, identifying those that included RWD. Each case was categorized based on the type and purpose of RWD use, sample size, FDA's evaluation, and label inclusion. A total of 129 orphan drugs were approved during this 5-year period, representing approximately 53% of all new drug approvals. Among these, 25 applications (19%) incorporated RWD, and 8 of them (32%) included RWD-derived findings in the product labeling. Among the 26 types of RWD usage, natural history studies were the most frequently employed (n = 14, 53.8%), followed by observational studies and Phase 3 trials utilizing external comparators. The primary purpose of RWD use was comparative evaluation (n = 19, 76%), and nearly half of the RWD data sets (n = 12, 48%) involved fewer than 100 patients. This study offers strategic insights into how RWD can be effectively leveraged in the development and regulatory approval of orphan drugs. The study offers practical guidance on designing regulatory-grade RWD studies and underscores key considerations for future submissions that aim to meet evidentiary standards in support of rare disease drug approvals.
Drug-induced QT-interval prolongation, a non-specific biomarker of increased risk for Torsades de Pointes (TdP), is a major safety concern in drug development. While in vitro hERG inhibition assays are required for early...Drug-induced QT-interval prolongation, a non-specific biomarker of increased risk for Torsades de Pointes (TdP), is a major safety concern in drug development. While in vitro hERG inhibition assays are required for early-phase screening, pharmacovigilance data from sources like the FDA Adverse Event Reporting System (FAERS) provide complementary insights. Integrating these heterogeneous data with molecular structure offers a promising, yet underutilized approach to predict proarrhythmic risk. We developed an interpretable graph neural network (GNN) framework integrating in vitro hERG inhibition data (PubChem AID 588834), FAERS-derived pharmacovigilance signals, and molecular structure information. Canonical SMILES were converted into molecular graphs using RDKit, and atom- and bond-level features were encoded. Four GNN architectures (GINE, GCN, GraphSAGE, and GATv2) were compared via stratified five-fold cross-validation. The best-performing model, GATv2, was further interpreted using Integrated Gradients to identify structural features contributing to QT liability. The final data set comprised 4,808 small molecules with binary QT-risk labels. GATv2 achieved a cross-validated ROC-AUC of 0.838, PR-AUC of 0.830, and F1-score of 0.756. Retraining on the full data set yielded ROC-AUC 0.918, PR-AUC 0.908, and F1-score 0.847. External validation on an independent hERG assay (AID 1671200, n = 2,405) confirmed strong performance (ROC-AUC 0.859, sensitivity 0.80, specificity 0.82). Atomic degree and hydrogen count were dominant predictors, consistent with known SARs. This GNN-based framework integrates structural and pharmacological data to predict QT risk, providing a transparent, structure-based decision-support tool aligned with ICH S7B/E14 and CiPA guidelines.
Campbell S, Nepal P, Daniel L
… +9 more, Wilson O, Dickson AL, Maizel J, Murray KT, Dupont WD, Hung A, Ray WA, Stein CM, Chung CP
Clin Pharmacol Ther
· 2026 Apr · PMID 41640183
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Pregabalin and duloxetine are widely prescribed non-opioid medications for chronic musculoskeletal pain. Pregabalin may increase the risk of heart failure, and duloxetine increases heart rate and blood pressure; however,...Pregabalin and duloxetine are widely prescribed non-opioid medications for chronic musculoskeletal pain. Pregabalin may increase the risk of heart failure, and duloxetine increases heart rate and blood pressure; however, little is known about their comparative cardiovascular safety. This study compared cardiovascular outcomes between new users of pregabalin and new users of duloxetine among US Veterans with chronic musculoskeletal conditions. We conducted a retrospective cohort study of US Veterans, aged 18-89 years, with chronic non-cancer musculoskeletal pain who started pregabalin or duloxetine between 2015 and 2021. Veterans with serious illnesses were excluded. The primary outcome was a major adverse cardiovascular event (MACE), a composite of acute myocardial infarction (AMI), stroke, heart failure (HF), or cardiovascular death. We identified cardiovascular events through Veterans Affairs and linked Medicare data and mortality data from the National Death Index. We adjusted for confounding through inverse probability of treatment weighting utilizing a propensity score incorporating 158 covariates. Outcomes were analyzed using Cox proportional hazard regression models. This study included 26,684 new users of pregabalin and 152,808 new users of duloxetine (83% male, 69% reported White race, median age = 56 years). During a total follow-up of 141,112 person-years, there were 1,798 total MACE events. The rate of MACE was higher for pregabalin users compared to duloxetine users (unadjusted HR: 1.61 (95% CI: 1.43-1.81), adjusted HR: 1.24 (95% CI: 1.08-1.41)), driven by higher rates of HF and AMI among pregabalin users. These findings present new considerations regarding the comparative cardiovascular safety of therapeutic options for chronic musculoskeletal pain.
Older adults with cirrhosis commonly experience chronic noncancer pain managed with chronic opioid therapy. Current guidelines recommend opioid deprescribing for high-risk populations, including in cirrhosis, but data on...Older adults with cirrhosis commonly experience chronic noncancer pain managed with chronic opioid therapy. Current guidelines recommend opioid deprescribing for high-risk populations, including in cirrhosis, but data on tapering and discontinuation are scarce. We described opioid discontinuation rates and identified predictors of tapering or discontinuation. This retrospective cohort study of Medicare fee-for-service beneficiaries (N = 800,763) ≥ 65 years with continuous opioid use for ≥ 90 days. The primary outcome was opioid discontinuation (i.e., a gap in refills > 30 days). The secondary outcome included opioid tapering (i.e., a 35% decrease in average daily morphine milligram equivalents; [yes/no]). The primary exposure was diagnosed cirrhosis severity (i.e., none, compensated, decompensated). We estimated discontinuation rates using the Kaplan-Meier method, time to opioid discontinuation using proportional hazards regression, and predictors of tapering with logistic regression. After 1 year, 37% (95% CI = 37-37%) of individuals without cirrhosis discontinued opioids, similar to those with compensated (36% (34-37%)) and decompensated (37% (35-39%)) cirrhosis. Age did not modify the adjusted association between cirrhosis status and discontinuation (Wald χ(4) = 7.72, p = 0.10) but calendar year (pre/post COVID-19) did (Wald χ(1) = 26.57, p < 0.001). This finding indicated higher deprescribing rates prior to the pandemic, especially for those without cirrhosis (HR, 1.32; 95% CI, 1.31-1.33) compared with those with cirrhosis (HR, 1.13; 95% CI, 1.06-1.20). Non-opioid analgesic use, fall history, and frailty significantly increased the odds of tapering. In conclusion, these findings may reflect a lack of safe analgesic alternatives or higher pain burden in cirrhosis.
Scott RK, Nachman S, Weld ED
… +5 more, Daley R, Atoyebi S, Bies R, Waitt C, Olagunju A
Clin Pharmacol Ther
· 2026 May · PMID 41626641
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Maternal health remains a critical global concern, particularly in underserved populations and in low- and middle-income countries where access to safe and effective therapeutics is limited. Despite the use of medication...Maternal health remains a critical global concern, particularly in underserved populations and in low- and middle-income countries where access to safe and effective therapeutics is limited. Despite the use of medications by most women during pregnancy, the exclusion of pregnant and lactating women from clinical trials has resulted in significant data gaps, hindering informed treatment decisions. As long-acting therapeutics transition into mainstream treatment and prevention strategies, it is critical to ensure these disparities are neither perpetuated nor widened. This review synthesizes insights from the maternal health session of the July 2025 workshop of the Community of Practice for Long-Acting Therapeutics in Maternal and Pediatric Health. It was convened and hosted by the University of Liverpool Centre of Excellence for Long-Acting Therapeutics with funding from Unitaid. Key themes explored during the session include (1) regulatory initiatives, research networks, and data infrastructures that are driving systemic change in maternal health research over the past two decades; (2) important efficacy and safety considerations during pregnancy and lactation using insights from long-acting antiretrovirals currently in clinical use; and (3) selected long-acting drug delivery systems with potential applications in maternal health. Starting with maternal health priorities, here we included further insights regarding long-acting injectable antipsychotics, long-acting reversible contraceptives, and the role of in silico modeling in bridging existing gaps. Several immediately actionable recommendations are presented on advancing long-acting therapeutics for maternal health priorities during pregnancy and lactation.