Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Orphan Designation for Drugs Approved in the United States and European Union: A Comparative Analysis.
Costa E, Ross JS, Kesselheim AS
Clin Pharmacol Ther · 2026 May · PMID 42218735 · Publisher ↗
Rare disease drugs represent a significant portion of new drug approvals, but the United States and European Union (EU) have differing approaches to Orphan Drug designations, impacting application fees and market exclusi...
Rare disease drugs represent a significant portion of new drug approvals, but the United States and European Union (EU) have differing approaches to Orphan Drug designations, impacting application fees and market exclusivity. This cross-sectional study analyzed the first rare disease drug approvals in the United States and EU from 2011 to 2020 using data from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) databases, describing similarities and differences in how both regions grant Orphan Drug designations. Out of 344 rare disease drug approvals, 336 (97.7%) were licensed by the FDA with Orphan Drug designations, 139 (40.4%) by the EMA with Orphan Drug designations; 131 (38.1%) were licensed with Orphan Drug designations by both the FDA and EMA, while 103 (29.9%) were approved in the EU without this designation. Additionally, 110 (32.0%) had approval from one agency only, with 102 (29.7%) by the FDA and 8 (2.3%) by the EMA. Both agencies were most consistent in granting Orphan Drug designations for advanced therapies (75.0%) and genetic diseases (55.4%). EMA approvals were lacking for tropical diseases (12.7%), while EU designations were often absent for diseases not considered distinct entities, such as subsets of cancers or pediatric indications of prevalent diseases. These findings reflect the differing regulatory frameworks and practices between the United States and the EU. Policymakers seeking to improve rare disease drug approval could prioritize incentives for the development of treatments for truly rare diseases as opposed to subsets of more common conditions for which incentives have already been established or create pathways that tackle scientific and societal challenges.
Piperacillin Population Pharmacokinetics in Plasma and Peritoneal Fluid and Dosing Optimization in Children Undergoing Liver Transplant: An Optimome Study.
de Cacqueray N, Oualha M, Foissac F … +12 more , Bournaud LF, Lui G, Bille E, Chardot C, Capito C, Lacaille F, Widmer P, Toubiana J, Tréluyer JM, Benaboud S, Bouazza N, Béranger A
Clin Pharmacol Ther · 2026 May · PMID 42216238 · Publisher ↗
Piperacillin-tazobactam is frequently used in children undergoing liver transplantation (LT), yet its pharmacokinetics (PK) in this population remains poorly characterized. We aimed to develop a population pharmacokineti...
Piperacillin-tazobactam is frequently used in children undergoing liver transplantation (LT), yet its pharmacokinetics (PK) in this population remains poorly characterized. We aimed to develop a population pharmacokinetic model for piperacillin in plasma and peritoneal fluid in children undergoing LT and to optimize dosing regimen for this population. We conducted a retrospective, single-center, observational study including all children receiving piperacillin-tazobactam as prophylaxis for LT and had at least one piperacillin concentration in both plasma and peritoneal fluid. PK analysis was conducted using nonlinear mixed effect modeling (Monolix) and was part of Optimome study. We included 31 patients with a median (range) age of 4 years (4 months-17 years). A total of 172 plasma and 146 peritoneal fluid samples were analyzed. Plasma concentrations were best fitted by a one-compartment model with first-order elimination. A virtual effect site compartment was added to adequately describe piperacillin concentrations in plasma and peritoneal fluid. Allometrically scaled body weight (pre-transplant and current values) and glomerular filtration rate (eGFR) were identified as significant covariates. Median (range) peritoneal/plasma AUC ratio was 72 (45-94) %. Simulations showed that optimal dosing regimens ranged from 300 mg/kg/day (q6h over 3 hours) to 400 mg/kg/day as a continuous infusion, depending on the PK target (i.e., fT or fT) and patient eGFR. In children undergoing LT, body weight and renal function explained some of the between subject variability for piperacillin PK. Higher dosing regimen combined with therapeutic drug monitoring is necessary to optimize exposure in plasma and at surgical site.
Prolonged cholinergic toxidrome with markedly low cholinesterase activity after exposure to emamectin benzoate emulsion: A case report.
Chubachi H, Kitazume N, Momo K … +1 more , Kamagata H
Int J Clin Pharmacol Ther · 2026 May · PMID 42210851 · Publisher ↗
Emamectin benzoate emulsion is a macrocyclic lactone insecticide that is not classified as an organophosphate or carbamate. We report the case of a man in his 80s with chronic kidney disease and cardiovascular comorbidit...
Emamectin benzoate emulsion is a macrocyclic lactone insecticide that is not classified as an organophosphate or carbamate. We report the case of a man in his 80s with chronic kidney disease and cardiovascular comorbidities who ingested emamectin benzoate emulsion. On day 2, he presented with abdominal pain, diarrhea, and marked sialorrhea; his vital signs were stable; however, his serum cholinesterase (ChE) had markedly declined (18 U/L). The patient was discharged with supportive care. From day 3, watery diarrhea recurred and neurobehavioral symptoms progressed. On day 5, he presented with pinhole miosis and further ChE suppression (2 U/L). Therefore, atropine was administered, and the patient was transferred for close monitoring. After discharge (day 8), miosis and sialorrhea persisted, and ChE remained low for weeks. Findings suggestive of tubular injury were observed during follow-up. The patients' symptoms resolved gradually, with ChE partially recovering by days 75 - 95. This case underscores the need for serial reassessment and structured follow-up after pesticide exposure, even when the patient appears stable at the initial presentation.
The Serotonin 2B (5-HT2B) Receptor: A Narrative Review of Preclinical and Clinical Evidence on the Safety Considerations and Therapeutic Potential for the Treatment of Depression.
Le GH, Wong S, Johnson DE … +6 more , Orsini DK, Zheng YJ, Teopiz KM, Dri CE, Rosenblat JD, McIntyre RS
Clin Pharmacol Ther · 2026 May · PMID 42209433 · Publisher ↗
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor-level treatment strategies beyond monoamine reuptake. The serotonin 5-HT2B...
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor-level treatment strategies beyond monoamine reuptake. The serotonin 5-HT2B receptor (5-HT2BR) is uniquely positioned at the interface of central-antidepressant mechanisms and peripheral cardiac risks. Herein, we reviewed preclinical, translational and clinical literature identified via PubMed and OVID (MEDLINE, Embase, AMED, PsychINFO) databases from inception to September 2025, supplemented by manual searches. Evidence converges that peripheral 5-HT2BR agonism is mechanistically linked to valvular heart disease (VHD) through mitogenic/profibrotic signaling in valve tissue, consistent with historical signals for anorectic agents (e.g., fenfluramine) and ergot-derived dopamine agonists, with supportive but limited data for 3,4-methylenedioxymethamphetamine (MDMA). Classical serotonergic psychedelics bind 5-HT2BRs; therefore, while contemporary dosing regimens are intermittent, cumulative exposure risks remain insufficiently characterized. Conversely, central 5-HT2BR signaling appears bidirectional wherein astrocytic 5-HT2BR activation under sustained serotonergic tone may support metabolic and plasticity programs, whereas neuronal 5-T2BR antagonism can normalize mesolimbic dopamine output and enhance medial prefrontal glutamatergic activity. Clinically, several approved antidepressant adjuncts (e.g., aripiprazole, brexpiprazole, cariprazine) display 5-HT2BR antagonism or inverse agonism and improve depressive symptoms without observed valvular signals in trials. The 5-HT2BR represents a tractable augmentation target for TRD provided that peripheral agonism is rigorously avoided. Consistent with evolving scientific and regulatory safety frameworks, we propose advancing centrally selective, periphery-sparing 5-HT2BR antagonists into biomarker-anchored early cardiac monitoring and preclinical exclusion of valve-cell 5-HT2BR agonism. This framework integrates central efficacy with defined safety boundaries, guiding development of mechanistically informed antidepressant therapies.
Clinical Validation of a QSP Model for ISB 2001, a Trispecific T Cell Engager to Support Optimal FIH Study Design in RRMM Patients.
Chandralayam Ayyappa Menon V, Matsuura T, Holkova B … +9 more , Gudi GS, Drake A, Pihlgren M, van der Graaf PH, Gn S, Garton A, Perro M, Konto C, Pacaud L
Clin Pharmacol Ther · 2026 May · PMID 42206665 · Publisher ↗
ISB 2001 is a trispecific antibody that binds to two tumor-associated antigens (TAA), CD38 and BCMA, and crosslinks to CD3 on T cells resulting in T cell-mediated cytotoxicity of tumor cells expressing these TAAs. ISB 20...
ISB 2001 is a trispecific antibody that binds to two tumor-associated antigens (TAA), CD38 and BCMA, and crosslinks to CD3 on T cells resulting in T cell-mediated cytotoxicity of tumor cells expressing these TAAs. ISB 2001 is currently being tested in relapsed and/or refractory multiple myeloma (RRMM) patients in the first-in-human (FIH) TRIgnite-1 study (NCT05862012). The CD3ε-binding domain of ISB 2001 does not cross-react with CD3 in cynomolgus monkeys. Therefore, no pharmacokinetic, efficacy, or toxicology data could be generated in a fully cross-reactive preclinical species to facilitate prediction of optimal FIH dose or the clinical efficacy dose range. For T cell engagers (TCEs), the minimum anticipated biological effect level (MABEL) approach is widely used to derive FIH doses. While this method is considered safe, this standard approach may result in starting doses that are sometimes too low to elicit meaningful clinical activity, potentially leading to several dose escalation cohorts at subtherapeutic levels in seriously ill patients. We used a novel quantitative systems pharmacology (QSP) model to inform FIH dose selection and predict the clinical efficacy dose range for ISB 2001. This modeling strategy enabled an efficient dose escalation design for the TRIgnite-1. This approach is consistent with the emerging FDA roadmap to reduce animal testing by utilizing computational modeling methodologies for FIH dose selection. Finally, we demonstrate the validation of the QSP model and approach by comparing its predictions with evolving preliminary safety, PK, and antimyeloma activity data from the ongoing TRIgnite-1 clinical trial.
Characterization of Lysosomal Hydrolases and Transporters and Their Age-Dependent Variability: Relevance to Drug Metabolism and Transport of Small Molecule and Biologic Drugs.
Gadara D, Singh DK, Subash S … +18 more , Yue G, Ahire D, Bohl C, Czerwinski M, Helmstetter S, Heyward S, Jones RS, Khojasteh C, Kikuchi R, Kulkarni P, Ma B, Murray B, Seib C, Smith B, Stresser DM, Taub ME, Wang T, Prasad B
Clin Pharmacol Ther · 2026 May · PMID 42198901 · Publisher ↗
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...
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.
Machine Learning Model Predicts Clinical Adverse Events of Small Molecule Kinase Inhibitors in Cancer Patients Using On-/Off-Target Engagement and Tissue Selectivity.
Jusko NM, Cao A, Sun D
Clin Pharmacol Ther · 2026 May · PMID 42191644 · Publisher ↗
Adverse events (AEs) of small molecule kinase inhibitors (SMKIs) at therapeutic doses in cancer patients are largely unpredictable in phase I-III studies and clinical use, despite extensive preclinical toxicity testing u...
Adverse events (AEs) of small molecule kinase inhibitors (SMKIs) at therapeutic doses in cancer patients are largely unpredictable in phase I-III studies and clinical use, despite extensive preclinical toxicity testing under good laboratory practice conditions. To address this gap, we developed a machine learning (ML) framework to predict the occurrence and time to onset of clinical AEs caused by SMKIs using on-/off-target engagement and tissue/cell selectivity. The analysis included 1939 unique AEs from 3,433 patients treated with 16 SMKIs. On-/off-target engagement was evaluated by linking the inhibition (Ki) constants and expression of 442 kinase targets to SMKI exposure, expressed as dose-normalized AUC across plasma and 36 tissues. For each AE, we constructed random survival forest models composed of ensembles of binary decision trees, evaluated predictive accuracy using the concordance index, and applied variable importance (VIMP) measures to identify kinase targets potentially responsible for tissue-specific AEs. The final models successfully predict the most common AEs (rash, nausea, fatigue, headache) along with the most severe hematological AEs (neutropenia, leukopenia, lymphopenia, thrombocytopenia, anemia). VIMP analyses highlighted previously unrecognized kinases potentially involved in tissue-specific AE profiles. External validation using data from a Phase II neratinib monotherapy trial demonstrated strong model performance, yielding Pearson correlation coefficients (PCCs) ≥ 0.87 between predicted and observed AE incidences. These findings show that integrating exposure, on-/off-target engagement, and tissue-specific selectivity enables robust prediction of the likelihood of SMKI-associated AEs for both blood- and organ-related toxicities, offering a scalable approach at both the patient- and population-level.
Bemnifosbuvir: An HCV NS5B Inhibitor With Multiple Modes of Action.
Zitzmann C, Ribeiro RM, Marc A … +2 more , Zhou XJ, Perelson AS
Clin Pharmacol Ther · 2026 May · PMID 42183606 · Publisher ↗
Bemnifosbuvir (BEM) is a potent, pan-genotypic inhibitor targeting the hepatitis C virus (HCV) NS5B polymerase. Its antiviral activity was evaluated in an ascending dose phase I clinical trial involving 30 patients treat...
Bemnifosbuvir (BEM) is a potent, pan-genotypic inhibitor targeting the hepatitis C virus (HCV) NS5B polymerase. Its antiviral activity was evaluated in an ascending dose phase I clinical trial involving 30 patients treated once a day for 7 days. After treatment initiation, plasma HCV RNA declined in a biphasic manner with a mean reduction of 2.3 log IU/mL after 24 hours and 4.4 log IU/mL by day 7 for the highest dose. Alanine aminotransferase (ALT) also normalized in most patients. We employed a multiscale mathematical model fitted to the HCV RNA and ALT dynamics to quantify the antiviral activity and evaluate the modes of action of BEM. We found that models in which BEM only acted as a typical HCV RNA polymerase inhibitor and reduced the intracellular production of HCV RNA did not fit the data as well as models in which BEM had multiple modes of action, including suppressing viral assembly and secretion and enhancing intracellular HCV RNA degradation. BEM's effectiveness in inhibiting intracellular HCV RNA production increased with dose (150 mg/day: 88.2%, 300 mg/day: 98.8%, 600 mg/day: 99.5%), while inhibition of viral assembly and release was ~95% effective regardless of dose. We observed a dose-dependent enhancement in the degradation of intracellular HCV RNA, with degradation rates 1.5-fold higher in patients receiving 300 mg/day and 2.7-fold higher in those receiving 600 mg/day than in patients receiving 150 mg/day. No significant differences in antiviral activity were detected between HCV genotypes 1b and 3 or between patients with and without compensated cirrhosis.
Cutaneous Adverse Drug Reactions Associated With BRAF and MEK Inhibitors: A Real-World Analysis of WHO Pharmacovigilance Data.
Sauer N, Giedziun P, Calik J … +1 more , Wiela-Hojeńska A
Clin Pharmacol Ther · 2026 Jul · PMID 42177750 · Full text
BRAF inhibitors and MEK inhibitors (MEKi) have reshaped the treatment of BRAF-mutant malignancies; however, cutaneous adverse drug reactions (ADRs) remain a frequent and clinically impactful toxicity. Although clinical t...
BRAF inhibitors and MEK inhibitors (MEKi) have reshaped the treatment of BRAF-mutant malignancies; however, cutaneous adverse drug reactions (ADRs) remain a frequent and clinically impactful toxicity. Although clinical trials provide insight into their safety profiles, real-world data on dermatologic ADRs are limited. We conducted a retrospective pharmacovigilance analysis of the WHO VigiAccess database, examining individual case safety reports (ICSRs) for seven BRAF and MEKi up to May 2025. Disproportionality analyses (reporting odds ratio (ROR), proportional reporting ratio (PRR), with 95% confidence intervals (CIs)) were performed for high-frequency dermatologic ADRs. Shannon entropy was used to assess the diversity of toxicity profiles across agents. Among 72,720 ICSRs, skin-related ADRs accounted for 39.78% of reports with vemurafenib, 16.49% with dabrafenib, and 14.62% with encorafenib. Among MEKi, the proportion of skin-related ADRs was highest for selumetinib (40.03%) and cobimetinib (34.31%). Rash was the predominant ADR across agents, but selumetinib demonstrated a significant disproportionality for dermatitis acneiform (ROR = 6.46, 95% CI [5.10, 8.18]). Photosensitivity reactions were most frequently reported with vemurafenib (11.31%) and cobimetinib (12.02%). Shannon entropy analysis identified two groups with differing ADR profile diversity: a higher-diversity group (cobimetinib, H = 3.66; dabrafenib, H = 3.60) and a lower-diversity group (trametinib, H = 3.51; binimetinib, H = 3.47); all cross-group comparisons were statistically significant after Holm-Bonferroni correction (p < 0.05). Chi-squared tests confirmed significant differences in skin ADR frequencies among agents (BRAF inhibitors: χ(2) = 1393.21, p < 0.001, Cramér's V = 0.255; MEKi: χ(3) = 1129.77, p < 0.001, Cramér's V = 0.175), with effect sizes indicating clinical relevance. Cutaneous ADRs are a defining toxicity of MAPK pathway inhibitors, with substantial interagent variability in frequency and phenotype. Real-world pharmacovigilance data underscore the necessity for agent-specific dermatologic monitoring strategies. Clinical pharmacists play a pivotal role in early ADR detection and management, enhancing adherence and optimizing therapeutic outcomes.
Anifrolumab Dose Regimen Selection for a Phase 3 Trial in Lupus Nephritis.
Almquist J, Chia YL, Tummala R … +4 more , Bertagnolli L, Jayne D, Tang W, Lindholm C
Clin Pharmacol Ther · 2026 May · PMID 42175562 · Publisher ↗
In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifr...
In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifrolumab, which abrogates type I interferon signaling, is an approved treatment for moderate to severe SLE. In a phase 2 trial in patients with LN (TULIP-LN; NCT02547922), promising clinical benefit was observed with an intensified regimen (IR) of intravenous anifrolumab (3× 900 mg Q4W, 300 mg thereafter) compared with the approved SLE dose (basic regimen [BR], 300 mg Q4W). Anifrolumab clearance was greater with higher levels of proteinuria; however, the quantitative relationship between proteinuria and anifrolumab exposure was not fully characterized. Here, we describe a mathematical model of time-varying anifrolumab pharmacokinetics, 24-hour urine protein-creatinine ratio (UPCR24), and investigational product discontinuation in patients with LN. The model evaluated both TULIP-LN anifrolumab dosing regimens (IR and BR) and revealed a temporal association between clearance and proteinuria in patients with LN, with each mg/mg UPCR reduction resulting in a 21% decrease in linear anifrolumab clearance. Our model indicated that an intensified regimen including 6 initial anifrolumab 900 mg doses provided adequate exposure and rapid UPCR24 reduction. Higher anifrolumab exposure and reduced UPCR24 were each associated with decreased risk of treatment discontinuation. These model results guided the selection of an optimized, longer intensified anifrolumab dosing regimen (6× 900 mg Q4W, 300 mg thereafter) for the ongoing phase 3 IRIS trial (NCT05138133).
From Classical PKPD to Model-Informed Drug Development: Are "Digital Twins" a New Paradigm?
Houk BE
Clin Pharmacol Ther · 2026 May · PMID 42168137 · Publisher ↗
Quantitative pharmacology has guided drug development for decades, turning concentration and response data into mechanistic models that support dosing, trial design, and regulatory decisions. Model-informed drug developm...
Quantitative pharmacology has guided drug development for decades, turning concentration and response data into mechanistic models that support dosing, trial design, and regulatory decisions. Model-informed drug development (MIDD) did not replace pharmacokinetic and pharmacodynamic (PKPD) modeling so much as formalize it across the lifecycle. Today, "digital twins" are often promoted as a new paradigm, yet most proposed features mirror established pharmacometrics: individual-level simulation, sequential updating, and decision-focused uncertainty analysis. The fundamentals remain unchanged, and identifiability still sets hard limits.
Pharmacokinetic evaluation of two oral formulations of chlorpromazine in healthy subjects.
Min HJ, Hwang JG, Choi YS … +1 more , Park MK
Int J Clin Pharmacol Ther · 2026 May · PMID 42163632 · Publisher ↗
Chlorpromazine is a first-generation antipsychotic agent that exerts its therapeutic effects primarily by antagonizing dopamine D2 receptors. This randomized, open-label, single-dose, two-period, two-sequence crossover s...
Chlorpromazine is a first-generation antipsychotic agent that exerts its therapeutic effects primarily by antagonizing dopamine D2 receptors. This randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted to evaluate the pharmacokinetic bioequivalence of two oral formulations of chlorpromazine 100 mg: Neomazine tablets (Whan In Pharmaceutical Co., Ltd.) and Chlorpromazine HCl tablets (Myung In Pharmaceutical Co., Ltd.). A total of 70 subjects were randomized, and 61 completed both treatment periods. Blood samples were collected at predefined intervals up to 72 hours post dose to assess pharmacokinetic parameters, including maximum plasma concentration (C) and the area under the plasma concentration-time curve to the last measurable concentration (AUC). Safety was assessed through monitoring of adverse events (AEs), clinical laboratory tests, vital signs, physical examinations, and 12-lead electrocardiograms. The geometric mean ratios (90% confidence intervals) for C and AUC were 1.0490 (0.9534 - 1.1542) and 0.9941 (0.9261 - 1.0671), respectively, falling within the accepted bioequivalence range of 0.80 - 1.25. Among the 70 subjects who received at least 1 dose, 116 AEs were reported in 48 individuals; all were mild in intensity and resolved without sequelae, and no serious AEs occurred. These findings confirm the pharmacokinetic bioequivalence and favorable tolerability of the two formulations under fasting conditions in healthy adults and support the use of Neomazine as a therapeutically equivalent and clinically interchangeable alternative to Chlorpromazine HCl.
Development of a pain intensity estimation model in breast cancer survivors using quantile regression: A nationwide claims-based cohort study.
Lee J, Chan A, Cho J … +1 more , Seo HJ
Int J Clin Pharmacol Ther · 2026 May · PMID 42163631 · Publisher ↗
OBJECTIVE: In patients in whom pain cannot be objectively evaluated, achieving high compliance with symptom management is challenging. This study aimed to estimate pain-related factors and pain intensity in patients with...
OBJECTIVE: In patients in whom pain cannot be objectively evaluated, achieving high compliance with symptom management is challenging. This study aimed to estimate pain-related factors and pain intensity in patients with breast cancer according to prescription history of analgesics. MATERIALS AND METHODS: Pain intensity was rated according to low, moderate, and high cumulative analgesic consumption score (CACS). CACS-based quantile regression analysis was performed considering sociodemographic (age, income, and disease duration), index-related (body mass index (BMI) and Charlson Comorbidity Index (CCI)), and surgery- and treatment-related variables. RESULTS: In the mild pain group (Q1), age (≥ 50 years; β = 0.5803) and BMI (≥ 25; β = 0.7062) -affected the pain estimate. In the moderate-pain group (Q2), age (≥ 50 years; β = 1.0380), BMI (≥ 25; β = 0.9011), CCI (≥ 3; β = 0.6106) and radiation therapy (yes; β = 0.5652) affected pain intensity. In the severe-pain group (Q4), age (≥ 50 years; β = 7.002), BMI (≥ 25; β = 6.2800), CCI (≥ 3; β = 3.4480), lymph node dissection (yes; β = 2.4420), and lymphedema (yes; β = 4.6580) affected pain estimate. CONCLUSION: Among patients with breast cancer, older age, longer disease duration, higher BMI and CCI, prior lymph node dissection, and lymphedema presence may contribute to more severe pain symptoms. These findings may pave the way for the development of preemptive pain intervention for patients with breast cancer.
Clinical Impact of Maximum Plasma Concentration of Busulfan in Pediatric Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation.
Bae S, Choi JY, Hong KT … +5 more , Kim BK, Park HJ, Yu KS, Rhee SJ, Kang HJ
Clin Pharmacol Ther · 2026 May · PMID 42151738 · Publisher ↗
Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure-toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent...
Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure-toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent allogeneic hematopoietic stem cell transplantation at Seoul National University Children's Hospital between 2009 and 2020 and received once-daily intravenous busulfan over four days (3-hour infusion, n = 122; 6-hour infusion, n = 212). Factors associated with toxicities were identified using multivariable logistic regression, and overall survival (OS) was evaluated by Kaplan-Meier and Cox regression analyses. Despite comparable exposures, the 3-hour infusion group showed higher C (4,260.2 vs 3,028.6 μg/L, P < 0.0001) and more frequent liver function test elevations (13.1% vs 0.5%, P < 0.0001). Receiver operating characteristic analysis identified a C cut-off of 4269.6 μg/L as a factor for hepatotoxicity. The 4-year OS was superior in the 6-hour infusion group (82.3% vs 71.9%, P = 0.02) and in the low C group (80.8% vs 66.5%, P = 0.01). Cox regression revealed C as an independent predictor of OS. A population PK model was developed using NONMEM. A 1-compartment model incorporating enzyme turnover auto-inhibition successfully described the busulfan PK profile. Simulations of published once-daily dosing regimens showed that extending the infusion to 6 hours successfully maintained C below the cut-off threshold. These results show that maintaining busulfan C below 4269.6 μg/L is associated with improved safety and survival. Prolonged infusion should be considered when adopting the busulfan once-daily regimen.
Biomarker-Based Prediction of OATP1B1 Activity in Clinical Routine-Investigating Coproporphyrins as Markers for Drug-Drug-Gene Interactions.
Potzel L, Zumtaugwald A, Bollinger A … +7 more , Jeiziner C, Hersberger KE, Wiss F, Lampert ML, Allemann SS, Meyer Zu Schwabedissen HE, Stäuble CK
Clin Pharmacol Ther · 2026 May · PMID 42145189 · Publisher ↗
Coproporphyrin I (CPI) is an established endogenous biomarker for detecting drug-drug interactions (DDIs) involving the hepatic uptake transporter Organic Anion Transporting Polypeptide 1B1 (OATP1B1, gene SLCO1B1). While...
Coproporphyrin I (CPI) is an established endogenous biomarker for detecting drug-drug interactions (DDIs) involving the hepatic uptake transporter Organic Anion Transporting Polypeptide 1B1 (OATP1B1, gene SLCO1B1). While CPI has been extensively studied in healthy volunteers using controlled pre- and post-OATP1B1-inhibitor sampling, its applicability in samples obtained in clinical routine from multimorbid, polymedicated patients remains poorly characterized. In this study, we evaluated whether single timepoint CPI concentrations obtained in clinical routine can be used to assess in vivo OATP1B1 activity by integrating genetic and pharmacological information. Serum CP levels were measured in patients undergoing pharmacist-led medication reviews following therapy failure or adverse drug reactions. CPI concentrations were analyzed in relation to genotype-predicted OATP1B1 phenotypes and exposure to drugs with potential impact on OATP1B1, which were identified following a previously published work by Stäuble et al., and their interaction with OATP1B1 was further evaluated with the herein presented in vitro transporter assay. CPI levels showed an association with drug intake and genotype-predicted phenotypes. Moreover, patients with decreased- or normal function phenotypes taking putative OATP1B1 inhibitors exhibited CPI levels comparable to patients carrying the poor-function or decreased-function phenotype without intake of such drugs, respectively, consistent with phenoconversion. These findings provide initial evidence that CPI may serve as an endogenous biomarker for identifying drug-drug-gene interactions in clinical routine to support a safer and more effective drug therapy. Furthermore, our data emphasize the need for further investigations in larger and more diverse patient populations to validate the findings on CPI.
Systems Pharmacology Approach to Paroxysmal Nocturnal Hemoglobinuria: Quantitative Framework for Biomarker Dynamics across Multi-Mechanistic Therapies.
Cruikshank A, Yang Y, Liu G … +2 more , Liu J, Zhu H
Clin Pharmacol Ther · 2026 May · PMID 42141707 · Publisher ↗
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder driven by complement-mediated destruction of red blood cells. Although complement inhibitors have transformed PNH management,...
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder driven by complement-mediated destruction of red blood cells. Although complement inhibitors have transformed PNH management, clinical responses vary across therapeutic classes because intravascular and extravascular hemolysis contribute differently to disease manifestations. Existing quantitative systems pharmacology (QSP) models of the complement system have improved understanding of PNH dynamics but primarily represent intravascular hemolysis and therefore do not fully explain biomarker patterns observed with all available treatments. In this study, we extend a published QSP model of the alternative complement pathway to incorporate mechanisms of extravascular hemolysis. The updated model integrates clinical pharmacokinetic and pharmacodynamic data from phase III trials of C5, C3, and factor B inhibitors and characterizes biomarker responses, including lactate dehydrogenase and circulating hemoglobin. By capturing both intravascular and extravascular processes, the model reproduces differences in therapeutic effects across complement inhibitor classes and provides a more complete mechanistic representation of complement-mediated hemolysis in PNH. The expanded model enables evaluation of drug targets throughout the complement cascade and supports prediction of biomarker dynamics, dose and regimen effects, and sources of patient variability. This work establishes a translational framework that can inform therapeutic development and guide the design of future studies for complement-mediated diseases.
Ten-Year Public Expenditure Savings Associated with TNF Inhibitor Biosimilars under Australia's Pharmaceutical Benefits Scheme.
Yiu CH, Ianni BD, Day RO … +2 more , Raubenheimer J, Lu CY
Clin Pharmacol Ther · 2026 May · PMID 42138454 · Publisher ↗
Biologic therapies are a major and growing driver of pharmaceutical expenditure globally, with tumor necrosis factor (TNF) inhibitors among the most widely used and costly biologics. In Australia, these therapies are fun...
Biologic therapies are a major and growing driver of pharmaceutical expenditure globally, with tumor necrosis factor (TNF) inhibitors among the most widely used and costly biologics. In Australia, these therapies are funded through the Pharmaceutical Benefits Scheme (PBS), where biosimilars offer lower cost alternatives; however, the long-term public expenditure impact of TNF inhibitor biosimilars under regulated pricing systems has not been comprehensively quantified. We conducted a retrospective, population-level expenditure analysis using publicly available PBS Item Reports data from 2015 to 2025 to estimate PBS cost savings associated with the listing of adalimumab, etanercept, and infliximab biosimilars for inflammatory arthritis. Counterfactual scenarios were constructed to estimate expected expenditure in the absence of biosimilar entry, explicitly accounting for key PBS pricing mechanisms, including mandatory price reductions and price-disclosure cycles. Biosimilar listing was associated with cumulative PBS savings of AU$562.3 million over the study period. Etanercept biosimilar generated the largest absolute savings (AU$341.5 million; 23.7% reduction), whereas adalimumab biosimilars generated smaller relative savings (AU$195.3 million; 9.4% reduction), reflecting delayed biosimilar entry despite high utilization. Most savings accrued in rheumatoid arthritis, followed by ankylosing spondylitis and psoriatic arthritis. In conclusion, TNF inhibitor biosimilars were associated with substantial and sustained reductions in public medicine expenditure in Australia. The magnitude of savings varied markedly by molecule and was jointly determined by the timing of biosimilar entry and statutory pricing mechanisms, illustrating how regulated reimbursement systems shape realized biosimilar value.
Regulation of Real-World Evidence in Rare Diseases in the MENA Region: A Review of Current Guidelines Compared to Global Frameworks.
Abdeljawad MM, Hamza N
Clin Pharmacol Ther · 2026 May · PMID 42138436 · Publisher ↗
Abstract loading — click title to view on PubMed.
Post-Approval Pediatric Use of Drugs Granted Waivers from Pediatric Testing.
Liu ITT, Savage TJ, Tsacogianis TN … +2 more , Kesselheim AS, Sarpatwari A
Clin Pharmacol Ther · 2026 May · PMID 42138424 · Full text
The Pediatric Research Equity Act mandates new drugs be tested in children before Food and Drug Administration (FDA) approval, though roughly one-fifth of these drugs are granted complete waivers from pediatric testing....
The Pediatric Research Equity Act mandates new drugs be tested in children before Food and Drug Administration (FDA) approval, though roughly one-fifth of these drugs are granted complete waivers from pediatric testing. With the high prevalence of these waivers, US children may be at risk of being treated by drugs without pediatric testing (and therefore with unclear risk-benefit profiles). We evaluated how often drugs granted pediatric testing waivers are prescribed in US children using a large commercial claims database. Using public FDA data, we identified drugs granted pediatric testing waivers from 2007 to 2022 that did not report pediatric testing prior to FDA approval. We used the Merative MarketScan Commercial Database to determine monthly pediatric users for the first 36 months after approval. We defined "pediatric users" as the number of unique pediatric patients with ≥1 dispensing in a month. Among 291 drugs granted waivers from pediatric testing, 147 (51%) had observable pediatric use in the first 3 years following approval. Median summed users was 17 (interquartile range [IQR], 3-102), with median 0.47 users/month (IQR, 0.08-2.83). Among the top 20 most-used drugs, pediatric users ranged from 508 (valsartan/hydrochlorothiazide) to 22,111 (conjugated estrogen cream) (median 1,050.5; IQR, 709.5-1,690.8), with a median of 29.2 users/month (IQR, 19.7-47.0). Among drugs granted waivers from pediatric trials, half have observable off-label use in children in the 3 years after FDA approval. Routine clinical use evidence from these prescriptions could be collected to inform drug labeling updates, and some drugs have sufficient use to make post-approval pediatric studies feasible.
Impact of CYP2C19 and CYP3A4 Inhibitor Use on Clopidogrel Clinical Effectiveness in CYP2C19 Genotyped Patients Undergoing Percutaneous Coronary Intervention.
Shao D, Malavé JG, Rossi JS … +6 more , Franchi F, Keeley EC, Angiolillo DJ, Stouffer GA, Cavallari LH, Lee CR
Clin Pharmacol Ther · 2026 May · PMID 42138382 · Publisher ↗
CYP2C19 and CYP3A4 contribute to clopidogrel bioactivation. CYP2C19 no-function alleles diminish clopidogrel's antiplatelet effects and clinical effectiveness. Coadministration of either a CYP2C19 or a CYP3A4 inhibitor m...
CYP2C19 and CYP3A4 contribute to clopidogrel bioactivation. CYP2C19 no-function alleles diminish clopidogrel's antiplatelet effects and clinical effectiveness. Coadministration of either a CYP2C19 or a CYP3A4 inhibitor may also reduce clopidogrel's antiplatelet effects and lead to phenoconversion in patients without a CYP2C19 no-function allele (normal/rapid/ultrarapid metabolizers: NM/RM/UMs). However, the impact of CYP2C19 or CYP3A4 inhibitor use on clopidogrel clinical effectiveness remains unclear. Rates of major atherothrombotic events (MAE) over 12 months after percutaneous coronary intervention (PCI) were evaluated in 3,242 patients across three sites who underwent CYP2C19 genotype testing and received P2Y inhibitor therapy. Overall, 6.8% of patients were co-prescribed a moderate or strong inhibitor of either CYP2C19 or CYP3A4, as defined by the U.S. Food and Drug Administration. In CYP2C19 genotype-predicted NM/RM/UMs treated with clopidogrel (n = 1,624), the MAE rates were numerically higher, but not significantly different in patients receiving either a CYP2C19 or a CYP3A4 inhibitor vs. no inhibitor (18.4 vs. 12.8 events/100 patient-years, adjusted hazard ratio (HR) 1.51, 95% confidence interval (CI), 0.85-2.68, P = 0.155). When evaluating CYP2C19 inhibitor and CYP3A4 inhibitor use separately, MAE rates were higher in clopidogrel-treated NM/RM/UMs receiving a CYP2C19 inhibitor compared to no inhibitor (adjusted HR 2.22, 95% CI 1.01-4.91, P = 0.048), but no significant difference was observed in those receiving a CYP3A4 inhibitor compared to no inhibitor (adjusted HR 1.26, 95% CI 0.57-2.75, P = 0.569). These results suggest that concomitant use of a CYP2C19 inhibitor, but not a CYP3A4 inhibitor, may contribute to phenoconversion and decreased clopidogrel clinical effectiveness after PCI in CYP2C19 genotype-predicted NM/RM/UMs.
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