Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Model-Informed Dosing Strategies for Epcoritamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma.
Liao X, Li T, Xu S … +7 more , Mohamed MF, Sinnollareddy M, Gupta M, Wielgos-Bonvallet M, Steele AJ, Sacchi M, Cao Y
Clin Pharmacol Ther · 2026 May · PMID 42138365 · Publisher ↗
Dose selection is a central challenge in drug development, and direct evaluation of alternative regimens is often ethically difficult. We developed a joint model integrating pharmacokinetics, pharmacodynamics, and Deauvi...
Dose selection is a central challenge in drug development, and direct evaluation of alternative regimens is often ethically difficult. We developed a joint model integrating pharmacokinetics, pharmacodynamics, and Deauville score to evaluate alternative dosing strategies for a CD3 × CD20 bispecific antibody, epcoritamab, as monotherapy in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after ≥2 lines of systemic therapy. The model was developed using clinical data from 165 patients and simultaneously described plasma epcoritamab concentrations, tumor burden dynamics, and longitudinal Deauville scores. Simulations were conducted in 1,000 virtual patients to evaluate three post-complete response (CR) dosing strategies: continuous, fixed-duration, and stop-at-CR. Responder subgroups were defined based on CR durability, and predictors of patients likely to require continuous treatment were explored. Simulations indicated that continued epcoritamab treatment after CR was associated with higher simulated CR rates over the long term, with simulated 2-year CR rates of 46.4% (continuous), 37.2% (fixed-duration), and 27.0% (stop-at-CR). Exploratory analyses suggested that indicators of residual disease, such as limited early tumor reduction and elevated circulating tumor DNA levels, help identify patients most likely to benefit from continuous treatment. This modeling framework provides a quantitative approach for evaluating alternative dosing strategies for epcoritamab monotherapy in R/R LBCL and supports the potential value of continuous therapy in maintaining long-term CR, as suggested by model-based simulations. However, this study focuses solely on efficacy outcomes; therefore, further validation and incorporation of safety outcomes are needed to fully support clinical decision-making and regimen optimization.
AI-Enabled Precision Dosing in Pediatrics: Enhancing Model-Informed Decision Making.
Irie K, Mizuno T
Clin Pharmacol Ther · 2026 May · PMID 42138351 · Publisher ↗
Ensuring safe and effective pharmacotherapy for children remains a central challenge in clinical pharmacology, yet rapid advances in AI have not translated into clinical practice. This Perspective highlights how AI-enabl...
Ensuring safe and effective pharmacotherapy for children remains a central challenge in clinical pharmacology, yet rapid advances in AI have not translated into clinical practice. This Perspective highlights how AI-enabled approaches can enhance model-informed decision making for precision dosing. By integrating pharmacometrics with pediatric digital twins and AI agents, these frameworks can enable physiologically grounded, adaptive, and learning-based dosing strategies. We outline a path from static prediction toward explainable, clinically actionable precision dosing in pediatric care.
Transcranial Magnetic Stimulation as a Translational Biomarker in Early-Phase Anti-Seizure Medication Development: A Randomized, Double-Blind, Placebo-Controlled Study in Generalized Epilepsy.
de Cuba CME, Ruijs TQ, de Goede AA … +5 more , Doll RJ, Juachon M, van Putten MJAM, Groeneveld GJ, Heuberger JAAC
Clin Pharmacol Ther · 2026 May · PMID 42129973 · Publisher ↗
One-third of epilepsy patients remain treatment-resistant, underscoring the need for novel anti-seizure medications (ASMs) and reliable biomarkers of central target engagement. Cortical hyperexcitability is a hallmark of...
One-third of epilepsy patients remain treatment-resistant, underscoring the need for novel anti-seizure medications (ASMs) and reliable biomarkers of central target engagement. Cortical hyperexcitability is a hallmark of epilepsy, making excitability a valuable pharmacodynamic biomarker for early-phase drug development supporting go/no-go decision making. Building upon prior transcranial magnetic stimulation (TMS) work in healthy participants, this study aimed to establish TMS-derived endpoints as translational biomarkers of ASM effects in patients. In a randomized, double-blind, placebo-controlled, two-way crossover design, patients with generalized epilepsy on levetiracetam (500 mg twice daily; n = 14) or valproic acid (≤1,000 mg/day; levetiracetam-naïve, n = 12) received a single oral dose of levetiracetam (2000 mg) or placebo. Participants were asked to refrain from their morning ASM dose to minimize background ASM levels while maintaining seizure protection. TMS combined with electromyography (EMG) and electroencephalography (EEG), and resting-state EEG were performed pre-dose, 1.5 h, and 3 h post-dose. Outcomes were analyzed using mixed-effects analysis of covariance or cluster-based permutation testing. Levetiracetam significantly reduced motor-evoked potential (MEP) amplitude, enhanced long-interval intracortical inhibition (LICI), and increased frontal gamma and beta power, with larger effect sizes in levetiracetam-naïve patients. These findings were further supported by linear concentration-response relationships for these endpoints. TMS-EEG revealed group-specific modulation: early TMS-evoked potential components (P30/N45) in levetiracetam patients vs. later components (N100/P180) in levetiracetam-naïve patients. These findings build upon prior results, demonstrating that TMS-based biomarkers are sensitive to levetiracetam's acute effects in epilepsy patients with MEP amplitude, LICI, and frontal beta/gamma power emerging as promising biomarkers, possible also for new ASM development.
Extracellular Vesicles as Immunotherapeutic Mediators in Gastrointestinal Cancers and Diseases: From Mechanisms to Clinical Translation.
Lin X, Zhang Y, Ma J … +9 more , Li J, Qin J, Jiang Y, Hu M, Huang H, Ren H, Cai S, Zhang S, Zhang H
Clin Pharmacol Ther · 2026 May · PMID 42129060 · Publisher ↗
Immunotherapy has transformed cancer treatment, yet its efficacy in gastrointestinal (GI) cancers and inflammatory diseases remains limited, underscoring the need for more effective immunomodulatory strategies. Multiple...
Immunotherapy has transformed cancer treatment, yet its efficacy in gastrointestinal (GI) cancers and inflammatory diseases remains limited, underscoring the need for more effective immunomodulatory strategies. Multiple biomaterial-based delivery platforms, including liposomes, polymeric nanoparticles, viral vectors, and inorganic nanocarriers, have been employed to enhance immune regulation and therapeutic transport. However, their clinical translation is hindered by intrinsic limitations such as immunogenicity, variable biocompatibility, nonspecific tissue distribution, payload instability, and challenges in scalable and reproducible manufacturing. These constraints highlight the need for safer and more clinically adaptable delivery systems. Extracellular vesicles (EVs), as naturally derived nanoscale carriers, have emerged as promising therapeutic tools due to their unique advantages, such as biocompatibility, low immunogenicity, precise targeting, and multifunctional molecular delivery. This review synthesizes recent advances in EV-based immunotherapeutic strategies for GI cancers and diseases, emphasizing approaches relevant to clinical pharmacology. Key innovations include EV vaccines, modulation of the immune microenvironment using cell source-specific EVs, and engineered EVs for the targeted delivery of cytokines, nucleic acids, or immune checkpoint inhibitors. Emerging applications involving EV-mediated transport of CAR constructs, oncolytic agents, and gene-editing tools further broaden their therapeutic potential. In conclusion, EV-based therapies offer transformative approaches through multimodal immune modulation and precision drug delivery to GI diseases. However, standardization, large-scale manufacturing, targeted delivery, and addressing tumor heterogeneity with personalized EV engineering will be crucial for clinical success in GI diseases. Overcoming these barriers will accelerate EV integration into next-generation immunotherapy and precision oncology.
Effect of Late Second to Early Third Trimester of Pregnancy on the Activity of Renal Organic Anion Transporters (OAT1 and OAT3): A Biomarker Study.
Thakur A, Unadkat JD, Fay EE … +2 more , Isoherranen N, Hebert MF
Clin Pharmacol Ther · 2026 May · PMID 42116706 · Publisher ↗
Pregnant individuals take drugs throughout pregnancy and many of these drugs (e.g., antivirals, antibiotics) are eliminated by renal organic anion transporters (OAT) 1 and OAT3. In vivo studies with OAT1/3 substrate drug...
Pregnant individuals take drugs throughout pregnancy and many of these drugs (e.g., antivirals, antibiotics) are eliminated by renal organic anion transporters (OAT) 1 and OAT3. In vivo studies with OAT1/3 substrate drugs suggest that pregnancy increases renal OAT1/3 activities by 1.5- to 1.8-fold. However, data from these in vivo studies are only available for some trimesters. Various endogenous metabolites (e.g., pyridoxic acid, glycochenodeoxycholate-3-sulfate (GCDCA-S)) have been identified as substrates of renal OAT1/3 and can potentially be utilized as phenotypic markers to study modulation of OAT1/3 activities across all trimesters of pregnancy. In this proof-of-concept study, we quantified the effect of late second to early third trimester (T2-T3) of pregnancy on the plasma concentration and renal clearance (CL) of OAT1/3 biomarkers. Targeted metabolomic analysis of paired plasma and urine samples (n = 46 pregnant women), collected during T2-T3 (25-29 weeks of gestation) and > 3 months postpartum (PP), was conducted. Average plasma concentrations of most OAT1/3 biomarkers were 27-43% lower in T2-T3 vs. PP. The CL ratios (T2-T3/PP) of biomarkers were 1.3-1.6, except for GCDCA-S and kynurenine where the ratios were ~5. The net renal secretory clearance and net unbound secretory clearance ratios of pyridoxic acid, p-cresol sulfate, p-cresol glucuronide, 3-indoxyl sulfate, and GCDCA-S were similar to the values listed above. Overall, OAT1/3 activity (as measured by endogenous biomarkers) is increased in T2-T3, consistent with available in vivo OAT1/3 substrate drug data. The studied biomarkers can be utilized in the future to quantify pregnancy-related changes in OAT1/3 transport activities across all trimesters.
Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is effective and safe in the treatment of hyperlipidemia in chronic kidney disease stage 3 - 4.
Zhu H, Chang Y, Jin Q
Int J Clin Pharmacol Ther · 2026 May · PMID 42112700 · Publisher ↗
AIMS: To evaluate the efficacy and safety of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in chronic kidney disease (CKD). BACKGROUND: Dyslipidemia is common in patients with CKD and con...
AIMS: To evaluate the efficacy and safety of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in chronic kidney disease (CKD). BACKGROUND: Dyslipidemia is common in patients with CKD and contributes to their elevated cardiovascular risk. However, evidence regarding the lipid-lowering efficacy and renal safety of PCSK9 inhibitors in CKD stages 3 - 4 is limited. MATERIALS AND METHODS: A cohort of 200 patients with stage 3 - 4 CKD and hyperlipidemia were administered evolocumab in a single-center retrospective study. Lipid parameters including low-density lipoprotein cholesterol (LDL-C), renal function (estimated glomerular filtration rate, serum creatinine, blood urea nitrogen), and liver enzymes were assessed at baseline and at 3, 6, and 12 months follow-up. Subgroup and multivariate analyses were performed to determine factors associated with LDL-C reduction. Publicly available transcriptomic resources were consulted to provide biological parameters regarding tissue-specific PCSK9 expression. RESULTS: After 12 months, LDL-C was significantly decreased (-56.3 ± 10.5%) compared to baseline where the reduction in stages 3 and stage 4 CKD were similar. Non-high-density lipoprotein (HDL-C) and total cholesterol also declined significantly, but here were no significant changes in HDL-C and triglycerides. Renal function showed no significant deterioration, and no hepatotoxicity or clinically significant adverse events occurred. Baseline LDL-C and age were independent predictors of LDL-C reduction. Public transcriptomic data indicated that PCSK9 expression is predominantly enriched in liver tissue but remains minimal in renal tissues and across major renal cell types, providing biological evidence to explain the preserved renal function observed in this cohort. CONCLUSION: Evolocumab is an effective agent for lowering LDL-C levels and has a satisfactory short-term renal and hepatic safety in this cohort with similar effects across CKD subgroups. The low renal expression of PCSK9 may partly explain its renal safety. These results support the use of evolocumab as a practical and well-tolerated lipid-lowering option for CKD patients who need intensive LDL-C control.
Fondaparinux to treat cerebral venous sinus thrombosis complicated by heparin-induced thrombocytopenia during puerperium: A case report and literature review.
Qi M, Feng X, Jiang L … +5 more , Wu C, Zhang X, Guo P, Wang N, Xu Y
Int J Clin Pharmacol Ther · 2026 May · PMID 42112699 · Publisher ↗
BACKGROUND: Cerebral venous sinus thrombosis (CVST) occurring during the puerperium is a rare yet life-threatening condition. The management of CVST becomes more complex when complicated by heparin-induced thrombocytopen...
BACKGROUND: Cerebral venous sinus thrombosis (CVST) occurring during the puerperium is a rare yet life-threatening condition. The management of CVST becomes more complex when complicated by heparin-induced thrombocytopenia (HIT), a prothrombotic adverse effect of heparin therapy. CASE PRESENTATION: A case of puerperium-associated CVST with HIT is presented, in which fondaparinux was utilized as an alternative anticoagulant during the acute phase, followed by rivaroxaban. A multidisciplinary approach was employed, which included hematoma drainage, decompressive craniectomy, and endovascular recanalization. The patient achieved a favorable outcome, with a modified Rankin scale score of 2 at the 3-month follow-up. CONCLUSION: This case highlights the potential safety and efficacy of fondaparinux in the management of CVST with HIT, emphasizing the critical role of a multidisciplinary approach in optimizing patient recovery.
Timing of antimicrobial stewardship intervention and mortality among patients admitted to intensive care unit.
Takuma A, Miura A, Tagami K … +1 more , Momo K
Int J Clin Pharmacol Ther · 2026 May · PMID 42112698 · Publisher ↗
OBJECTIVES: Antimicrobial stewardship is important in the intensive care unit (ICU), where critically ill patients are managed. Herein, we aimed to evaluate the associations between the timing of antimicrobial stewardshi...
OBJECTIVES: Antimicrobial stewardship is important in the intensive care unit (ICU), where critically ill patients are managed. Herein, we aimed to evaluate the associations between the timing of antimicrobial stewardship team (AST) interventions in the ICU and patient mortality and to identify the optimal timing of interventions to improve patient survival. MATERIALS AND METHODS: We retrospectively analyzed the data of patients admitted to the ICU at Showa Medical University Northern Yokohama Hospital (April 2016 - March 2023). The primary outcome was in-hospital mortality; the key exposure was the timing of AST intervention following antimicrobial initiation. Mortality incidence rates per 100 person-days and age-adjusted incidence rate ratios were calculated. RESULTS: Overall, 94 patients were included. Earlier AST intervention after ICU admission was associated with the lowest mortality (incidence rate (IR): 0.205 (95% confidence interval (CI): 0 - 0.512) per 100 person-days). In an age-adjusted analysis, later intervention was associated with a higher mortality incidence rate than earlier intervention (IR ratio (IRR): 5.53 (95% CI: 1.30 - 23.50), p = 0.02). CONCLUSION: Earlier AST intervention after ICU admission was associated with lower mortality in ICU patients. Proactive and timely stewardship efforts are therefore needed in ICUs.
Uncovering Coenzyme Q10-Related Genetic Determinants of Statin-Associated Muscle Symptoms: Evidence from the UK Biobank and the All of Us Research Program.
Lee DH, Park YA, Song Y … +4 more , Han JM, Choi KH, Kim MG, Gwak HS
Clin Pharmacol Ther · 2026 May · PMID 42109163 · Publisher ↗
Statin-associated muscle symptoms (SAMS) are frequent adverse effects of statin therapy and have been hypothesized to result from impaired coenzyme Q10 (CoQ10) biosynthesis. Although genetic determinants of CoQ10 levels...
Statin-associated muscle symptoms (SAMS) are frequent adverse effects of statin therapy and have been hypothesized to result from impaired coenzyme Q10 (CoQ10) biosynthesis. Although genetic determinants of CoQ10 levels have been reported, genome-wide association studies (GWASs) conducted specifically in statin users are lacking. Moreover, direct CoQ10 measurements are unavailable in large-scale proteomic resources, necessitating suitable proxy biomarkers. COQ7, a key enzyme in the late steps of CoQ10 biosynthesis, was used as a proxy for CoQ10 biosynthetic capacity. We performed a GWAS of COQ7 protein levels in statin-treated participants from the UK Biobank. The lead variant was evaluated for association with SAMS in an independent cohort of statin users from the All of Us, followed by replication in an independent SAMS cohort from the UK Biobank. Gene-statin interaction analyses were conducted to assess statin-specific genetic effects. In addition, polygenic risk score (PRS) analyses were performed using previously reported CoQ10-associated variants from non-statin-specific cohorts. The GWAS identified the lead variant, rs66554427, with the A allele associated with lower COQ7 protein levels (β = -0.13, SE = 0.018, P = 1.1 × 10). In the All of Us, the rs66554427 A allele was associated with an increased risk of SAMS (OR = 1.27, 95% CI: 1.16-1.39, P = 5.16 × 10). These findings were consistently replicated in the UK Biobank SAMS cohort (OR = 1.23, 95% CI: 1.06-1.43, P = 6.89 × 10). Significant additive and multiplicative interactions between statin and rs66554427 were observed (P < 0.001). PRS analyses further demonstrated that genetically predicted lower CoQ10 levels were associated with a higher risk of SAMS. Using COQ7 protein levels as a proxy for CoQ10 biosynthesis, we identified statin-specific genetic susceptibility to SAMS and supported a causal role of impaired CoQ10 biosynthesis in SAMS.
Prediction of Acute Liver Injury Trajectory in Patients Following Acetaminophen Overdose: A Multibiomarker Machine Learning Proof-of-Concept Study.
Humphries C, Kilpatrick AM, Scullion KM … +6 more , Aird R, Bruce L, Candela ME, Man TY, Forbes SJ, Dear JW
Clin Pharmacol Ther · 2026 May · PMID 42109121 · Publisher ↗
Clinical translation of novel therapies can be hindered by heterogeneity-driven sample size inflation in late-stage trials. In acetaminophen-induced liver injury (APAP DILI), many patients recover spontaneously, diluting...
Clinical translation of novel therapies can be hindered by heterogeneity-driven sample size inflation in late-stage trials. In acetaminophen-induced liver injury (APAP DILI), many patients recover spontaneously, diluting investigational drug efficacy signals. We developed a prognostic enrichment tool to identify patients with worsening injury trajectories for more efficient trial designs. Biomarker model discovery and evaluation used serum samples from three UK cohorts: the MAPP2 APAP DILI biobank (n = 147), an independent pre-intervention evaluation cohort from the ongoing MAIL trial (n = 34), and healthy controls (n = 13). We measured 63 biomarkers and evaluated 321,682 combinations using kernel naïve Bayes classification to predict liver injury trajectory (ALT rising vs. falling). Sensitivity analysis using patient-level grouped cross-validation showed combining multiple biomarkers while constraining collinearity was necessary to maximize performance. A four-biomarker model (MCSFR, WBC, Sodium, K18) achieved AUC 0.868 (derivation) and 0.854 (evaluation). When optimized for prognostic certainty, the model yielded a Positive Likelihood Ratio of 14.4, increasing the Positive Predictive Value for worsening injury from a baseline of 29.4% to 85.7%. Time-dependent cost-minimization modeling for a hypothetical phase 3 trial identified an application threshold (sensitivity 80.0%, specificity 91.7%, Number Needed to Screen 3.4) as the global economic optimum, resulting in an illustrative trial cost reduction from $39.0 M to $8.3 M. This proof-of-concept demonstrates multidimensional biomarker models can resolve signal dilution. Distinguishing patients destined for injury progression reduces sample size requirements, which could de-risk novel therapy development.
Clinical Model-Informed Precision Dosing Consult Service for Accelerating Personalized Medication in Pediatric Patients.
Taylor ZL, Nadai T, Irie K … +10 more , Tan WR, Parikh S, Hosawi A, van Hoogdalem MW, Morales Junior R, Tang Girdwood S, Leino AD, Mizuno K, Vinks AA, Mizuno T
Clin Pharmacol Ther · 2026 May · PMID 42108662 · Publisher ↗
Traditional dosing strategies often rely on a "one-size-fits-all" paradigm, assuming an "average" patient with typical demographic and pharmacological characteristics. In reality, this often overlooks existing between-pa...
Traditional dosing strategies often rely on a "one-size-fits-all" paradigm, assuming an "average" patient with typical demographic and pharmacological characteristics. In reality, this often overlooks existing between-patient variability and can lead to suboptimal drug exposure or toxicity. This issue is especially pronounced in pediatric patients, who experience rapid growth and development of organ functions. Although patient's age and body size are often considered when determining pediatric dose, those factors account for only a relatively small part of the variability. Pharmacometrics provides a rigorous framework for characterizing drug behavior, uncovering patient-specific covariates driving variability, and allows translating insights derived from adults to pediatric populations. Model-informed precision dosing (MIPD) integrates quantitative pharmacological models to leverage clinical data from patients (e.g., drug concentrations and biomarkers) to predict drug exposure and response, thereby informing optimal dosing strategies to maximize clinical benefits. While MIPD has demonstrated feasibility and clinical benefits, it remains underutilized in routine clinical practice. In this article, we describe the establishment and operation of an MIPD consultation service within an academic children's hospital. Through real-world examples, we illustrate how precision dosing workflows can be integrated into routine clinical care and highlight key considerations for further dissemination. By sharing our experience, we aim to bridge a critical gap in the literature and provide a practical blueprint for operationalizing MIPD to advance personalized therapy in pediatrics.
A Systematic Review on Disease-Modifying Therapies in Parkinsonian Disorders.
Eijsvogel PPNM, Smits LMG, Kremer PHC … +1 more , Groeneveld GJ
Clin Pharmacol Ther · 2026 May · PMID 42104724 · Publisher ↗
Parkinsonian disorders, including Parkinson's disease, Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy, are progressive neurodegenerative conditions with no treatment options to slow disea...
Parkinsonian disorders, including Parkinson's disease, Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy, are progressive neurodegenerative conditions with no treatment options to slow disease progression. This systematic review provides an overview of evidence of disease-modifying therapies that have been evaluated in clinical studies across these disorders, based on a comprehensive literature search up to May 2025. Eligible studies included clinical trials investigating pharmacological interventions aimed at slowing disease progression. Most clinical development has focused on Parkinson's disease, with limited progress in other Parkinsonian disorders. Therapies targeting alpha-synuclein, such as monoclonal antibodies and small molecules, have shown target engagement but limited clinical efficacy. Glucocerebrosidase-enhancing agents, particularly ambroxol, demonstrated promising biomarker and clinical signals in early-phase trials. Glucagon-like peptide-1 receptor agonists and kinase inhibitors have yielded mixed results, with some agents progressing to phase 3 trials. Neurotrophic factors, cell survival and neuroprotective therapies, stem cell therapies, and anti-inflammatory agents remain largely investigational, with limited evidence of efficacy. Repurposed drugs, including memantine and riluzole, have shown preliminary signals of benefit, though confirmatory trials are lacking. Despite substantial research efforts, no disease-modifying therapy has been approved for any Parkinsonian disorder. The heterogeneity of disease mechanisms and the limitations of current clinical endpoints, such as the Unified Parkinson's Disease Rating Scale, underscore the need for biomarker-driven approaches and stratified trial designs. Future success will likely depend on improved patient selection, mechanistic targeting, and the integration of fluid and imaging biomarkers to demonstrate disease modification.
Balancing Reassurance and Vigilance: Real-World Evidence in Post-Marketing Drug Safety.
Wang YC, Standing JF
Clin Pharmacol Ther · 2026 Jun · PMID 42104211 · Publisher ↗
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Registered Clinical Trials of Ayahuasca and DMT: A Scoping Review.
Stojanović T, Nilsson KW, Fredriksson R … +2 more , Schiöth HB, Moulin TC
Clin Pharmacol Ther · 2026 Jul · PMID 42104189 · Full text
Interest in ayahuasca and its main component, N,N-Dimethyltryptamine (DMT), has currently moved from historical and experimental use into modern clinical development. Yet, current evidence is fragmented, and systematic m...
Interest in ayahuasca and its main component, N,N-Dimethyltryptamine (DMT), has currently moved from historical and experimental use into modern clinical development. Yet, current evidence is fragmented, and systematic mapping of trial methods and design choices remains limited. We therefore systematically examined registered interventional trials of DMT, ayahuasca, and DMT combined with harmine on ClinicalTrials.gov, identifying 26 eligible trial registers for review. We extracted and harmonized trial characteristics, participant eligibility and enrollment patterns, design features, administration routes, and registered outcomes, and linked completed registrations to associated publications. The registry landscape expanded after 2020-2021 and was dominated by early-stage development, with most trials in phase I and more than half listed as completed at the time of extraction. Trials were primarily DMT-only and most often sponsored by academic or hospital institutions. Eligibility criteria were conservative, emphasizing medically and psychiatrically healthy adult cohorts and extensive cardiovascular and psychiatric exclusions. Accordingly, primary outcomes prioritized acute safety and physiological monitoring, alongside structured characterization of the subjective and altered-states profile, while disorder-specific symptom endpoints were less commonly prioritized as primary objectives. Publications linked to included trials largely reflect this early-stage focus, describing controlled administration, tolerability limits, route and formulation refinement, and initial mechanistic readouts. A smaller set of publications from depression-focused trials provides preliminary evidence of potential clinical effects, supporting further controlled replication and broader disorder-focused development. Overall, registered trials indicate an active and maturing field that has generated foundational safety and regimen knowledge, but remains constrained by a limited number of indication-specific programs beyond depression.
Why Pediatric CAR-T Therapies Still Lag Behind: Insights from Six Treatments Centrally Approved in Europe.
Hanquet L, Dogné JM, Musuamba FT
Clin Pharmacol Ther · 2026 Jul · PMID 42101305 · Full text
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Discontinuing Long-Term Denosumab in Treating Fragile Bone: Why, for Whom, and How?
Lu KH, Lin RC, Chang IL … +3 more , Fu SH, Tsai MY, Yang SF
Clin Pharmacol Ther · 2026 May · PMID 42101135 · Publisher ↗
Discontinuation of denosumab (Dmab) may be necessary due to adverse events or an unfavorable long-term risk-benefit profile. However, accumulating evidence demonstrates pronounced rebound phenomena after withdrawal, most...
Discontinuation of denosumab (Dmab) may be necessary due to adverse events or an unfavorable long-term risk-benefit profile. However, accumulating evidence demonstrates pronounced rebound phenomena after withdrawal, most notably a marked increase in multiple vertebral fractures, and, in some reports, elevated mortality. This review addresses three key clinical considerations: (1) the mechanistic and clinical evidence for rebound effects and indications for Dmab cessation ("Why?"); (2) patient populations in whom Dmab initiation or continuation may be inappropriate and who therefore require careful transition planning ("For whom?"); and (3) optimal discontinuation and sequential treatment strategies, including scenarios in which continued or lifelong therapy may be advisable ("How?"). Emerging data suggest that concurrent teriparatide and zoledronate may attenuate rebound risk in long-term Dmab users requiring urgent discontinuation, although prospective validation is needed before routine adoption.
A Comment about AI Methods that May Help Advance Pharmacovigilance.
Anderson MK, Kane-Gill S, Boyce RD
Clin Pharmacol Ther · 2026 Jul · PMID 42101007 · Publisher ↗
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Artificial Intelligence for Regulatory Evidence: A Systematic Document Analysis of European Medicines Agency Regulatory Advice and Public Reports.
Nollen LM, van Westen GJP, Westman G … +1 more , Pasmooij AMG
Clin Pharmacol Ther · 2026 Jul · PMID 42095708 · Full text
Artificial intelligence (AI) is receiving increasing attention across the entire lifecycle of medicines, from early development to postauthorization use. While various AI tools have been developed in commercial and acade...
Artificial intelligence (AI) is receiving increasing attention across the entire lifecycle of medicines, from early development to postauthorization use. While various AI tools have been developed in commercial and academic settings, the extent of their use in regulatory contexts within the European Union remains unknown. In this study, we systematically analyzed the use of AI for regulatory evidence by reviewing Public reports and internal development advice documents from the European Medicines Agency (EMA). Of 26,480 documents screened, 52 documents contained AI use, reflecting 43 unique AI tools used across quality, nonclinical, clinical, and pharmacovigilance domains. The majority of AI tools were deployed in clinical applications, and outputs were used either directly as endpoints, in shaping clinical trial methodology, or in ancillary analyses. Comments and advice from the EMA regarding AI use varied according to the context of use and covered aspects of documentation, methodology, validation, and lifecycle management. Our findings indicate that AI use in regulatory evidence is still limited but showing an increasing trend. As the field is still novel, there are limited regulatory precedents, and AI-specific guideline development and harmonization across regulatory jurisdictions are still ongoing. In this light, the quantitative characterization of AI tools and AI-related regulatory comments captured in this analysis provide concrete insights into AI use and frequent regulatory considerations, aiding in both AI tool and AI guideline development.
Machine Learning Prediction of Unbound Ceftriaxone Concentrations in Children: Capturing Developmental Changes in Protein Binding for Precision Dosing.
Tang BH, Li QY, Sun J … +7 more , Zhou Y, Hao GX, Wang XJ, van den Anker J, Zhao W, Liu YY, Sun DQ
Clin Pharmacol Ther · 2026 Jul · PMID 42095663 · Publisher ↗
The pharmacological activity of antimicrobial agents depends on unbound concentrations, but accurately estimating these free fractions remains challenging in pediatric patients due to developmental protein binding change...
The pharmacological activity of antimicrobial agents depends on unbound concentrations, but accurately estimating these free fractions remains challenging in pediatric patients due to developmental protein binding changes. This study aimed to develop a machine learning (ML) model to predict unbound ceftriaxone concentrations using routinely available clinical variables while capturing nonlinear developmental effects. A total of 176 paired total/unbound ceftriaxone concentrations and routine clinical variables from neonates, infants, and children were used to train ten ML algorithms. The optimal model was evaluated in an independent real-world cohort and compared with two established mathematical equations. The ExtraTrees Regressor achieved the best predictive performance, with a root mean square error (RMSE) of 6.95 μg/mL and an R of 0.87. Using only routine variables, including total ceftriaxone concentration, serum albumin, weight, and age, the model accurately estimated unbound ceftriaxone concentrations across a wide range of pediatric patients (0-12 years). Real-world validation further confirmed its robustness, yielding a mean absolute percentage error (MAPE) of 28.9% and outperforming both reference equations, with reductions in MAPE of 14.2% and 14.7% relative to the empirical In vivo and disease-adapted equations, respectively. Application of the final model to a virtual pediatric population aged 0-12 years revealed a nonlinear age-dependent protein binding pattern, characterized by low and variable binding in neonates, rapid maturation during early infancy, and stabilization after 2 years of age. By incorporating these maturational effects, the ML model provides a practical tool for predicting unbound drug exposure, facilitating individualized dosing and precision medicine in pediatric patients.
A Review of Virtual Twins in Physiologically-Based Pharmacokinetic Modeling and Simulation.
Mannix E, Mostafa S, Rostami-Hodjegan A … +2 more , Polasek TM, Kirkpatrick CMJ
Clin Pharmacol Ther · 2026 May · PMID 42095647 · Publisher ↗
The novel application of Virtual Twins (VT) in PBPK (VT-PBPK) presents the opportunity to advance precision dosing and accelerate the shift from one-size-fits-all to targeted, individualized treatments. This review aims...
The novel application of Virtual Twins (VT) in PBPK (VT-PBPK) presents the opportunity to advance precision dosing and accelerate the shift from one-size-fits-all to targeted, individualized treatments. This review aims to: (1) critically evaluate existing research on the use of VTs in PBPK, (2) develop a conceptual definition of VT-PBPK, (3) describe and evaluate VT methodological diversity, (4) examine existing regulatory frameworks and guidance governing the integration of VT-PBPK, and (5) identify opportunities and challenges for advancing next-generation VTs. A structured literature search was conducted to identify studies describing VT-PBPK of a whole human body for the purpose of predicting drug concentration and/or effect. Details of the VT-PBPK models and VT design were extracted from each study. A framework assessing and categorizing methods of simulation and virtualization was applied to the extracted data. Twenty-two (22) studies were included which demonstrated the application of VT-PBPK across a range of populations, disease states, and drug classes. All studies applied VT-PBPK to real-world patient-specific covariate data retrospectively for the purpose of PBPK model development and evaluation, or model-informed precision dosing (MIPD). In the VT approaches, three levels of virtualization were identified; low, medium, and high, as determined by the number of covariates integrated into the model. To date there is no specific regulatory guidance on the appropriate use of VT-PBPK. A shift in application of PBPK modeling from population-based to specific, individualized predictions is required to advance VTs toward clinical implementation. Achieving rigorous design and evaluation of VT models will require strong interdisciplinary collaboration.
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