Clinical Pharmacology And Therapeutics[JOURNAL]
Sun
200 papers
Quantification of Age and Sex Ratio Differences between Trial and Target Population for New Drugs.
Serra-Burriel M, Schlossmacher P, Vokinger KN
Clin Pharmacol Ther · 2026 Apr · PMID 41622752 · Full text
Clinical trials are essential to understand the benefit-harm profile of new drugs. Lack of adequate representation in age and sex ratio in clinical trials can result, for example, in higher side effects for underrepresen...
Clinical trials are essential to understand the benefit-harm profile of new drugs. Lack of adequate representation in age and sex ratio in clinical trials can result, for example, in higher side effects for underrepresented patients. We quantified differences in age and sex ratios between trial and target populations of new drugs approved by the FDA 2011-2022. We used the FDA's database to identify all new drugs and pivotal randomized trials. Information for average age and sex ratio was obtained from clinicaltrials.gov. Each trial's indication was matched with prevalence estimates of the targeted diseases from the global burden of disease study. A total of 458 drugs (773 trials) were included. The trial populations were significantly younger, on average 4.8 years (95% CI [5.4 years, 4.2 years]), and the female ratio significantly smaller, on average 4.3 percentage points (95% CI [5.4 pp, 3.3 pp]), than the target populations. For diseases with average patient age below 40, the trial population was significantly older than the target population but significantly younger 40 years and older. For diseases with average age between 30 and 39, the female ratio in the trial population was significantly higher than in the target population but significantly lower 50 and older. Better age and sex ratio representation in the trial population is indicated to improve safety and efficacy for patients. Trials targeting diseases below 40 should enroll younger participants and increase their male ratio, while the opposite is true for trials targeting diseases with an older age.
Causal Effects of Hydrophilic Bile Acids on Carfilzomib-Related Cardiovascular Events in Multiple Myeloma: A Mendelian Randomization Study.
Shabnaz S, Farber-Eger E, Tantawy M … +13 more , Shahisavandi N, Garrett TJ, Rubinstein SM, Fradley MG, Alomar ME, DeAvila D, Shain KH, Cornell RF, Lenihan D, Lu Q, Wells QS, Baz RC, Gong Y
Clin Pharmacol Ther · 2026 Jun · PMID 41622719 · Full text
Carfilzomib is highly effective in the treatment of multiple myeloma, but it has been associated with cardiovascular adverse events that impact patient outcomes. Our prior global metabolomic analyses indicated an associa...
Carfilzomib is highly effective in the treatment of multiple myeloma, but it has been associated with cardiovascular adverse events that impact patient outcomes. Our prior global metabolomic analyses indicated an association between hydrophilic bile acids and carfilzomib-cardiotoxicity risk, although a causal relationship remained to be determined. Here, our objective was to validate the previously identified bile acids in an independent cohort and investigate whether these hydrophilic bile acids play a causal role in carfilzomib-cardiotoxicity using Mendelian randomization. Using targeted metabolomics, we validated the association between glycoursodeoxycholic acid and carfilzomib-cardiotoxicity in an independent cohort (n = 61). We then performed two-sample Mendelian randomization analyses, using metabolome-wide association study results to provide the genetic instruments for bile acid levels as exposure and genome-wide association study summary statistics from the UK Biobank (n = 484,598) as the outcome data for cardiovascular adverse events. Causal inference was assessed with the inverse-variance weighted method, followed by multiple sensitivity analyses. Higher glycoursodeoxycholic acid concentration (odds ratio = 0.34, P = 0.032) was associated with lower cardiotoxicity risk after adjusting for hypertension and high levels of brain natriuretic peptides. Mendelian randomization analysis demonstrated a robust causal effect of glycoursodeoxycholic acid on cardiotoxicity risk (β = -0.00065, P = 6.2 × 10). Gene enrichment analysis indicated pathways involving potassium channel regulation and thromboxane signaling to be implicated. This integrative metabolomic and genetic investigation supports a potential protective role of glycoursodeoxycholic acid in cardiovascular vulnerability and motivates larger, carfilzomib-specific studies to evaluate its utility for risk stratification.
Pharmacokinetic Evaluation of a Cinnamon Product on CYP2A6 Substrate Drugs: Application of a Novel Tool Involving the Nicotine Metabolite Ratio.
Nguyen AP, Hadi DL, Todd DA … +6 more , Manwill PK, White JR, Layton ME, Cech NB, Thummel KE, Paine MF
Clin Pharmacol Ther · 2026 Jun · PMID 41622703 · Full text
Cinnamon (Cinnamomum spp.) is used as a culinary spice and dietary supplement. A major constituent, cinnamaldehyde, was previously shown to inactivate cytochrome P450 (CYP) 2A6 in vitro. A mechanistic static model predic...
Cinnamon (Cinnamomum spp.) is used as a culinary spice and dietary supplement. A major constituent, cinnamaldehyde, was previously shown to inactivate cytochrome P450 (CYP) 2A6 in vitro. A mechanistic static model predicted an ~5-fold increase in the AUC of the CYP2A6 substrates nicotine and letrozole. Accordingly, the effects of a well-characterized cinnamon (Cinnamomum verum) product on the pharmacokinetics of nicotine and letrozole were evaluated in 16 healthy, non-nicotine using adults. They were administered a single dose of nicotine gum (2 mg) or letrozole tablet (2.5 mg) (baseline). After a sufficient washout (2-14 days), they self-administered C. verum (2 g thrice daily) for 5 consecutive days. On Day 6, they were administered C. verum with nicotine or letrozole, followed by two more doses of C. verum (cinnamon exposure). Plasma was collected from 0 to 12 (nicotine) or 0-240 (letrozole) hours. The geometric mean plasma concentration vs. time profile for both drugs was nearly superimposable in the presence vs. absence of C. verum. The geometric mean ratio (GMR) [90% confidence interval] of the AUC of nicotine and letrozole in the presence to absence of cinnamon was 0.98 [0.96-1.12] and 1.11 [0.98-1.24], respectively (P > 0.16), indicating no interactions. Application of the "slope approach" involving the 3-hydroxycotinine-to-cotinine ratio provided potential new mechanistic insight into CYP2A6 inhibition. The general lack of effect of a typical dosage of C. verum on the pharmacokinetics of nicotine and letrozole suggests that C. verum may be safe to consume with both drugs, as well as other CYP2A6 substrates.
Clinical Study to Evaluate Drug Interactions of Cannabidiol with Citalopram and Morphine in Healthy Adults.
Salcedo P, Volpe DA, Chaturbedi A … +9 more , Shah A, Krishna A, Hyland PL, Vegesna G, Hsiao CH, De Palma R, Fein M, Rouse R, Florian J
Clin Pharmacol Ther · 2026 Apr · PMID 41622700 · Full text
Cannabidiol (CBD) is one of the most abundant bioactive cannabinoids. Research has demonstrated CBD's ability to inhibit metabolic enzymes like cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), potentially lea...
Cannabidiol (CBD) is one of the most abundant bioactive cannabinoids. Research has demonstrated CBD's ability to inhibit metabolic enzymes like cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), potentially leading to drug interactions. However, clinical knowledge gaps remain, particularly with regard to drugs that are more commonly taken by consumers of unregulated CBD products. This study aimed to characterize the effects of daily CBD consumption, at doses typical of unregulated CBD products, on the pharmacokinetics of citalopram and morphine. These two commonly prescribed medications are metabolized by CYPs and UGTs, respectively. This open-label, sequential study involved two cohorts of 20 healthy participants. Cohort one received a single dose of citalopram (20 mg) on days 1 and 13, with CBD (2.5 mg/kg twice daily) administered for 12 days. Cohort two received a single dose of morphine (15 mg) on days 1, 4, and 11, with CBD (2.5 mg/kg twice daily) given for 9 days. The geometric mean ratio (GMR, [90% confidence interval]) for citalopram with and without CBD for 12 days was 1.43 (1.34-1.52) for the area under the plasma concentration-time curve (AUC) and 1.12 (1.06-1.17) for the maximum observed plasma concentration (C). The GMR for AUC and C for morphine coadministered with CBD compared to morphine alone was 1.06 (0.96-1.16) and 1.19 (1.05-1.35), respectively. For morphine with CBD for 9 days compared to morphine alone, the GMR for AUC and C was 1.12 (1.00-1.26) and 1.11 (0.94-1.30), respectively. While a significant pharmacokinetic interaction between CBD and citalopram was observed, interactions between CBD and morphine, as well as its metabolites, were limited.
PKRxiv: A Best Practice Model for Advancing Pharmacoequity Through Open Pharmacokinetic Data Sharing.
Atoyebi S, Venkatasubramanian P, Akinloye A … +4 more , Eniayewu O, Best BM, Else L, Olagunju A
Clin Pharmacol Ther · 2026 May · PMID 41620928 · Full text
Model-informed drug development is increasingly integrated across the drug development continuum, enabling more efficient, cost-effective, and targeted trials while reducing reliance on animal studies. Achieving pharmaco...
Model-informed drug development is increasingly integrated across the drug development continuum, enabling more efficient, cost-effective, and targeted trials while reducing reliance on animal studies. Achieving pharmacoequity requires not only equitable access to medicines but also to the data and knowledge that inform drug development and regulatory decisions. To address challenges in pharmacokinetic data sharing, PKRxiv (https://pkrxiv.org/) was developed as a discipline-specific repository designed around Findable, Accessible, Interoperable, Reusable (FAIR) principles. This tutorial introduces PKRxiv's rationale, design, data submission and access workflows, and practical use cases. Available datasets at the end of September 2025 include over 5,500 individual drug concentration-time data points from over 900 unique participants across 3 continents. The platform supports structured submission of pharmacokinetic, pharmacogenetic, and safety/efficacy data, with persistent digital object identifiers for discoverability and citation. Contributors can apply one of three data sharing models-unrestricted, noncommercial, or contributor-controlled-with optional embargo periods. Users can explore datasets using the Data Explorer or Data Cards, or submit requests after providing a statement of intended use case. It enables pooling of datasets across multiple studies. Recommendations to help advance the field are proposed as data sharing becomes more widely expected: obtaining consent for unspecified future research use of data, sharing data underlying peer-reviewed publications as standard practice, including discipline-specific repositories in data management plans, and incentivizing post-approval data sharing by industry. Supporting data from all therapeutic areas and population groups, PKRxiv is a critical step toward a more transparent, equitable, and collaborative future in clinical pharmacology research.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update.
Maillard M, Schwab M, Whirl-Carrillo M … +16 more , Moyer AM, Suarez-Kurtz G, Pui CH, Stein CM, Klein TE, Spahn C, Kwon S, Hartono JL, de Boer NK, Ahmad T, Antillon-Klussmann FG, Caudle KE, Kato M, Yeoh AEJ, Schmiegelow K, Yang JJ
Clin Pharmacol Ther · 2026 Apr · PMID 41618934 · Full text
Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no-function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and p...
Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no-function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines. Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry. In this updated guideline, we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes (updates on www.clinpgx.org).
Longitudinal Tumor Size and Survival Modeling for Exposure-Response Analysis of Drugs with Frequent Dose Reductions: Dose Justification of Abemaciclib in Patients with Metastatic Breast Cancer.
Chigutsa E, Chapman SC, Turner PK
Clin Pharmacol Ther · 2026 Apr · PMID 41589906 · Full text
Abemaciclib is an oral anticancer drug indicated for treatment of HR+ HER2- breast cancer. Dose modifications due to side effects are frequent, thus drug exposures change over time as a result of altering the dose or tem...
Abemaciclib is an oral anticancer drug indicated for treatment of HR+ HER2- breast cancer. Dose modifications due to side effects are frequent, thus drug exposures change over time as a result of altering the dose or temporarily withholding abemaciclib treatment. This limits the utility of simple exposure-response assessments (such as Kaplan-Meier quartile analyses) using static summary pharmacokinetic measures of drug exposure. The objective of the current work was to characterize the exposure-response relationship of abemaciclib using nonlinear mixed-effects modeling in 663 patients with metastatic or advanced breast cancer. A time-course joint simultaneous pharmacokinetic-tumor size-progression-free survival model accounted for changes in drug exposure due to dose reductions/omissions and described the change in tumor size over time. The change in tumor size was a highly significant predictor of the hazard for progression-free survival in a joint tumor size-time to event model (P < 0.001). Interval censoring was used in the time to event model to account for wide patient visit intervals. Simulations using the combined pharmacokinetic-tumor size-time to event model demonstrated the adequacy of a 150 mg twice daily dose in combination with fulvestrant. There was a negligible impact of dose reductions on efficacy, likely due to the shallow exposure-response relationship. When analyzing survival data where the drug exposure changes significantly within an individual over time, it is important to maximize the use of available longitudinal data through simultaneous modeling of time-course tumor size and survival data.
Measuring the Impact of the Substitution of Innovator Biologics With Biosimilars on Uptake and Costs Among Ontario Public Drug Benefit Recipients.
Iacono A, Ho MKH, Yang J … +8 more , Campbell T, Wynne W, Shearer D, Andersen L, Majer E, Ledlie S, Tadrous M, Gomes T
Clin Pharmacol Ther · 2026 Jun · PMID 41589765 · Full text
In Ontario, biologics have historically represented a small proportion of public drug claims but a large proportion of spending. Biosimilars, lower cost alternatives to biologics, offer a potential solution to the rising...
In Ontario, biologics have historically represented a small proportion of public drug claims but a large proportion of spending. Biosimilars, lower cost alternatives to biologics, offer a potential solution to the rising spending on biologics. From March 2023 to January 2024, the Ontario Ministry of Health required public drug program beneficiaries on eight innovator biologics to transition to biosimilars. Clinicians were reimbursed for supporting patients who transitioned. To evaluate the impact of this biosimilar switch policy, we conducted a repeated cross-sectional study using administrative data from April 2019 to June 2024. For the biologics (innovator and biosimilar) included in the policy, we reported the biosimilar market share, public drug program spending, and clinician support fees. We used interrupted time series analyses to evaluate the policy's impact, and forecasting to estimate drug cost savings. From March 2023 to June 2024, the percentage of affected individuals on biosimilars increased from 21.7% to 96.5%. Drug cost savings were $65.2 million between April 2023 to June 2024, with most savings attributed to non-insulin biosimilars. We estimated savings of $46.6 million in Year 1 (April 2023 to March 2024) and $95.9 million in Year 2 (April 2024 to March 2025). Clinician support fees totaled $3.4 million across the study period. Ontario's biosimilar policy achieved high biosimilar uptake and substantial cost savings. Future research should examine the impact of this policy on clinical outcomes to assess its broader implications for patient care and long-term sustainability.
Population Pharmacokinetics of Clesrovimab in Preterm and Full-Term Infants.
Hu Z, Hellmann F, Zang X … +6 more , Plock N, Parmar K, Railkar RA, Cheung SYA, Maas BM, Gheyas F
Clin Pharmacol Ther · 2026 Apr · PMID 41589687 · Full text
Clesrovimab is a half-life extended monoclonal antibody targeting the respiratory syncytial virus fusion protein. Three studies (phase Ib/IIa [MK-1654-002], phase IIb/III [CLEVER], and phase III [SMART]) were conducted t...
Clesrovimab is a half-life extended monoclonal antibody targeting the respiratory syncytial virus fusion protein. Three studies (phase Ib/IIa [MK-1654-002], phase IIb/III [CLEVER], and phase III [SMART]) were conducted to evaluate the efficacy, safety, and pharmacokinetics (PK) of clesrovimab in infants. The objectives of this analysis were to develop an infant population PK model for clesrovimab and to evaluate the influence of intrinsic and extrinsic factors on clesrovimab PK in infants. A total of 5850 samples from 2942 participants were included in the population PK analysis. A two-compartment model with first-order absorption and elimination well described clesrovimab PK in infants. The estimated half-life for clesrovimab was 44.0 days. Clearance, absorption rate constant, and central volume of distribution had low inter-individual variability. Body weight was included as a covariate on all clearance and volume parameters, with estimated allometric scaling exponents centered on a body weight of 5 kg. A maturation function further described the change in clearance with increasing infant age. In addition to body weight and maturation function, the final model contained an effect of race on clearance. Although body weight, age, and race were identified as statistically significant covariates, the magnitude of the effect of these covariates on clesrovimab exposures was small (< 30%). The results of the population PK modeling support intramuscular administration of clesrovimab for the prevention of respiratory syncytial virus (RSV) disease in all infants, including healthy infants and infants at increased risk for severe RSV disease.
GLP-1 receptor agonists as adjunct therapy in hidradenitis suppurativa: A hypothesis.
Feily A
Int J Clin Pharmacol Ther · 2026 May · PMID 41582649 · Publisher ↗
Abstract loading — click title to view on PubMed.
Hemoglobin A1c levels in patients with type 2 diabetes mellitus receiving oral semaglutide with versus without proton pump inhibitors: An exploratory study.
Matsunuma S, Hirota Y, Yoshimoto K
Int J Clin Pharmacol Ther · 2026 May · PMID 41582648 · Publisher ↗
OBJECTIVE: Oral semaglutide contains salcaprozate sodium, which promotes the opening of epithelial tight junctions and increases gastric pH to prevent its degradation; these actions together improve absorption. Proton pu...
OBJECTIVE: Oral semaglutide contains salcaprozate sodium, which promotes the opening of epithelial tight junctions and increases gastric pH to prevent its degradation; these actions together improve absorption. Proton pump inhibitors (PPIs) increase gastric pH. However, it is unclear whether PPIs affect the absorption of semaglutide and may therefore enhance the blood glucose lowering effect of semaglutide or affect the reduction of hemoglobin A1c (HbA1c). Therefore, this study investigated differences in HbA1c changes and adverse events between those with and without PPI co-administration. MATERIALS AND METHODS: This single-center retrospective study included patients with type 2 diabetes who received oral semaglutide. Patients were categorized into two groups: those on treatment with PPI (w/PPI) and those not on treatment with PPI (without PPI (w/o PPI)). The primary outcome was the change in HbA1c levels at 52 weeks, while the secondary outcomes included changes at 26 weeks and the incidence of adverse events. RESULTS: A total of 66 patients were included. HbA1c reduction at 52 weeks was significantly greater in the w/PPI group (-1.56 ± 0.37%) than in the w/o PPI group (-1.08 ± 0.76%, p = 0.024). The incidences of adverse events were 24.0% and 31.7% in the w/PPI and w/o PPI groups, respectively (p = 0.502). CONCLUSION: HbA1c reduction at 52 weeks was significantly greater in the PPI co-administration group than in the group without PPI. Future research should include larger sample sizes and pharmacokinetic studies to clarify the clinical implications and interactions between oral semaglutide and PPIs.
Epidemiological characteristics of severe skin adverse reactions caused by immune checkpoint inhibitors based on case reports.
Tang SN, Ma XW, Zhang XY … +6 more , Zhang NN, Wang F, Ye FL, Chen NN, Yang P, Zhu NN
Int J Clin Pharmacol Ther · 2026 May · PMID 41582647 · Publisher ↗
OBJECTIVE: To investigate the epidemiological characteristics of severe cutaneous adverse reactions (cirAEs) induced by immune checkpoint inhibitors (ICIs) and to provide evidence for the rational clinical use of ICIs an...
OBJECTIVE: To investigate the epidemiological characteristics of severe cutaneous adverse reactions (cirAEs) induced by immune checkpoint inhibitors (ICIs) and to provide evidence for the rational clinical use of ICIs and pharmacovigilance for cutaneous toxicities. MATERIALS AND METHODS: We systematically searched the PubMed, MEDLINE, EMBASE, CNKI, and Wanfang databases using keywords including "immune checkpoint inhibitors," "cutaneous adverse reactions," "cutaneous toxicity," "induced," and "case," and their combinations to identify detailed case reports on cirAEs. Data on patient demographics (sex and age), primary cancer type, ICI use, time to cirAE onset, cirAE severity grading, and reaction classification were extracted. Descriptive statistics, co-occurrence analysis of clinical manifestations, and the Apriori algorithm were employed to analyze cirAE patterns. RESULTS: The analysis included a total of 120 articles involving 126 patients (male: 80; female: 46) with a mean age of 63.05 ± 11.85 years. The highest incidence was observed in patients aged 60 - 69 years. The primary cancers were predominantly non-small cell lung cancer and melanoma. Programmed death 1 (PD-1) inhibitors were the most commonly used therapeutic agents. The median time to onset was 15 - 28 days. Most cases were classified as severe Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). CONCLUSION: Healthcare professionals must remain vigilant for severe cirAEs and ensure timely diagnosis and management to safeguard patient safety during ICI therapy.
Emulating Comparative Oncology Trials With Real-World Evidence Studies (ENCORE): Process Development and Methodological Considerations for Oncology Real-World Data.
Weberpals J, Schneeweiss S, Kehl KL … +17 more , Rivera DR, Mishra-Kalyani P, Lerro CC, Larkins E, Narayan P, Curley R, Hahn G, Anand P, Natanzon Y, Belli AJ, Wang CK, Collins J, Kish J, Espirito J, Robert NJ, Glynn RJ, Wang SV
Clin Pharmacol Ther · 2026 Apr · PMID 41577635 · Publisher ↗
Real-world evidence (RWE) is increasingly used to complement findings from randomized controlled trials (RCTs), contextualizing the effectiveness and safety of medical interventions as delivered in routine clinical pract...
Real-world evidence (RWE) is increasingly used to complement findings from randomized controlled trials (RCTs), contextualizing the effectiveness and safety of medical interventions as delivered in routine clinical practice. Advances in the curation and accessibility of electronic health record (EHR) data present the opportunity to utilize real-world data (RWD) to investigate therapeutic areas including oncology, where administrative healthcare claims databases alone are often not fit-for-purpose. The RCT DUPLICATE initiative has previously evaluated when RWE can most appropriately draw causal conclusions by emulating trials for nononcology indications. Here, we present the design and trial selection for the emulation of comparative oncology trials with real-world evidence (ENCORE) project, which extends this work to oncology. ENCORE is designed to emulate 12 RCTs in four oncology-specialized EHR databases across four different cancer indications, specifically non-small-cell lung cancer, breast cancer, colorectal cancer, and multiple myeloma. It will place special emphasis on systematic evaluation of fitness of data in relation to the study design and statistical analysis for a particular research question and preregistration of study protocols prior to initiation and analysis. Prespecified criteria will assess agreement of treatment effect estimates between RCTs and their respective emulations. Through extensive sensitivity analyses benchmarked against RCT results, the ENCORE project aims to inform understanding of how measurement, design, and analytic decisions influence the interpretation of results from emulated oncology trials using RWD.
Population Pharmacokinetic and Exposure-Efficacy Analysis of Baloxavir Marboxil for Influenza Treatment and Post-Exposure Prophylaxis in Children.
Retout S, De Buck S, Gaudreault J … +4 more , Jolivet S, Duval V, Cosson V, Delporte ML
Clin Pharmacol Ther · 2026 Apr · PMID 41566882 · Full text
Baloxavir acid (baloxavir), the active metabolite of the prodrug baloxavir marboxil, is a selective inhibitor of the influenza virus cap-dependent endonuclease. The population pharmacokinetic (popPK) profile of baloxavir...
Baloxavir acid (baloxavir), the active metabolite of the prodrug baloxavir marboxil, is a selective inhibitor of the influenza virus cap-dependent endonuclease. The population pharmacokinetic (popPK) profile of baloxavir in adults/adolescents has been described previously. To characterize the PK of baloxavir in patients aged ≥1 year, a popPK model was developed using data from 1,795 patients across six studies, including miniSTONE-2 (NCT03629184) in which children aged 1 to <12 years received a bodyweight-based single oral dose of baloxavir marboxil (2 mg/kg, <20 kg; 40 mg, ≥20 kg) for treatment of influenza. The final popPK model was a 2-compartment model with first-order absorption and elimination processes and an absorption lag time; the most influential covariates affecting baloxavir exposure were bodyweight and race (Asian versus non-Asian). Pediatric-to-adult exposure matching for PK parameters relevant for treatment and post-exposure prophylaxis (PEP) indications were used to support pediatric label extensions. Adequate exposure matching was demonstrated between non-Asian pediatric patients using the miniSTONE-2 dose and non-Asian adult patients. After dosing optimization, predicted baloxavir exposures in Asian pediatric patients using the miniSTONE-2 dose were similar to exposures in Asian adults. To bridge PEP efficacy data from the BLOCKSTONE study in Japanese pediatric patients (JapicCTI-184,180) to non-Asian patients aged ≥1 year, an exposure-matching approach between Japanese pediatric patients receiving the lower BLOCKSTONE dose and non-Asian pediatric patients receiving the miniSTONE-2 dose was employed. Together, these observations indicate that the recommended miniSTONE-2 dosing regimen is likely to be efficacious for treatment and PEP in children aged 1-<12 years, regardless of race.
Real-World Outcomes of Pembrolizumab Monotherapy in Metastatic Non-Small Cell Lung Cancer by Age and Sex: A National Population-Based Study in Australia.
Yiu CH, Clarke SJ, Lu CY
Clin Pharmacol Ther · 2026 May · PMID 41566161 · Publisher ↗
Lung cancer remains the leading cause of cancer-related mortality globally. While immune checkpoint inhibitors (ICIs) are the standard of care for metastatic non-small cell lung cancer (NSCLC), real-world data from Austr...
Lung cancer remains the leading cause of cancer-related mortality globally. While immune checkpoint inhibitors (ICIs) are the standard of care for metastatic non-small cell lung cancer (NSCLC), real-world data from Australia are limited. We conducted a population-based cohort study using national Pharmaceutical Benefits Scheme and National Death Index data, accessed via the Australian Bureau of Statistics DataLab. Adults initiating pembrolizumab monotherapy for metastatic NSCLC (2017-2022) were included. Overall survival (OS) and time to treatment discontinuation (TTD) were assessed using Kaplan-Meier analyses and multivariate Cox regressions. Immune-related adverse events (irAEs) were inferred from incident corticosteroid and levothyroxine prescriptions. Subgroup analyses were performed by age (18-64 and ≥ 65) and sex. Among 4,334 patients, median OS was 13.2 months. Younger patients had longer OS than those ≥ 65 (17.9 vs. 12.4 months; adjusted hazards ratio [aHR] 1.29, 95% confidence interval [CI]: 1.18-1.41). Females had longer OS than males (14.8 vs. 12.1 months; aHR 0.89, 95% CI: 0.83-0.96). TTD did not differ significantly by age or sex. Incident corticosteroid and levothyroxine use occurred in 19.1% and 8.0% of patients, respectively, with higher levothyroxine use in females (9.8% vs. 6.7%, P < 0.001). In this real-world study, survival outcomes with pembrolizumab were shorter than those reported in clinical trials. Observed differences by age and sex in survival and irAE proxies suggest potential biological variation in treatment response and toxicity. These findings highlight the need for integrated clinical data to support personalized use and inform treatment strategies that improve outcomes across diverse populations.
Untargeted Metabolomics Identifies N-Lactoyl-Amino Acids as Dose-Responsive Plasma Biomarkers of Metformin Adherence in Type 2 Diabetes.
Cajka T, Hricko J, Rudl Kulhava L … +10 more , Paucova M, Novakova M, Hola V, Rakusanova S, Fiehn O, Skop V, Lankova I, Miskova I, Pelikanova T, Haluzik M
Clin Pharmacol Ther · 2026 Apr · PMID 41556311 · Full text
Metformin is the most widely prescribed antidiabetic drug, yet adherence remains difficult to objectively assess. Using untargeted metabolomics and lipidomics, we analyzed plasma from 637 patients with type 2 diabetes (T...
Metformin is the most widely prescribed antidiabetic drug, yet adherence remains difficult to objectively assess. Using untargeted metabolomics and lipidomics, we analyzed plasma from 637 patients with type 2 diabetes (T2D) with confirmed metformin use and 143 nondiabetic controls, annotating 614 metabolites. Patients were stratified by plasma metformin into sub-therapeutic, therapeutic, and supra-therapeutic groups, and associations were evaluated by multiple linear regression and composite metabolite ranking. Five previously unannotated features were structurally identified as N-lactoyl-amino acids, whose levels correlated strongly with plasma metformin (ρ = 0.42-0.55, P < 0.0001) and increased up to 7.2-fold in the supra-therapeutic group (> 2000 ng/mL). While N-lactoyl-amino acids were consistently detected in the nanomolar range, they still displayed robust and dose-dependent associations with metformin. Broader metabolic changes in T2D included elevated lactate, organic acids, and branched-chain amino acids, together with reduced urea cycle metabolites. Lipidomics showed increases in saturated triacylglycerols and diacylglycerols and decreases in cholesteryl esters, sphingomyelins, and phospholipids. These findings establish N-lactoyl-amino acids as robust, dose-responsive plasma biomarkers of metformin exposure. Despite being up to four orders of magnitude less abundant than their amino acid precursors, they sensitively reflect mitochondrial lactate overflow and pharmacodynamic adaptation, offering objective assessment of adherence.
Straight to Phase III: Model-Informed Approach Speeds Depemokimab Clinical Development in Interleukin-5-Driven Diseases.
Zecchin C, Schalkwijk S, Pouliquen IJ … +4 more , Berges A, Bird N, Follows R, Austin D
Clin Pharmacol Ther · 2026 Apr · PMID 41556088 · Full text
IL-5, a key mediator of type 2 inflammation, underlies various diseases, including severe asthma, CRSwNP, EGPA, and HES. Reduction in blood eosinophil count (BEC), a biomarker of IL-5 activity, is commonly used to evalua...
IL-5, a key mediator of type 2 inflammation, underlies various diseases, including severe asthma, CRSwNP, EGPA, and HES. Reduction in blood eosinophil count (BEC), a biomarker of IL-5 activity, is commonly used to evaluate the efficacy of anti-IL-5 biologic therapies. Model-informed drug development (MIDD) and quantitative decision making (QDM) were used to shorten the clinical development of depemokimab (an ultra-long-acting anti-IL-5 biologic). A Bayesian nonlinear mixed effects dose-time response model predicted the depemokimab dose in severe asthma achieving comparable BEC reductions to those observed in mepolizumab (an approved anti-IL-5 biologic) Phase III MUSCA and MENSA trials. Prespecified QDM go/no-go criteria were applied to assess success probability. Phase IIb efficacy-based trial simulations were conducted using negative binomial distribution to simulate individual annualized exacerbation rate. A depemokimab PK/PD (BEC) model predicted Phase III trial doses in CRSwNP/EGPA/HES. Single depemokimab doses were well-described by the Bayesian model; a single depemokimab dose ≥ 60 mg had probability ≥ 80% of exceeding Minimum (78%; MUSCA) and ≥ 10% probability of exceeding Target (84%; MENSA) values for trough BEC reduction from baseline vs. placebo. Clinical trial simulations demonstrated < 3% probability of more precise estimation of the Phase III dosing regimen with a conventional efficacy-based dose-ranging study. Depemokimab 100 mg for severe asthma/CRSwNP and 200 mg for EGPA/HES, administered subcutaneously every 26 weeks, were selected for Phase III trials. MIDD and QDM shortened the depemokimab development program by 2-3 years, emphasizing the potential of this approach for progressing new therapies from Phase I directly to Phase III.
Liberty on Odaiba, Against the Silhouette of Tokyo Bay: Inspirations for Moving Hypothesis-Generating Research to Patient-Centered Therapeutics.
Venkatakrishnan K
Clin Pharmacol Ther · 2026 Feb · PMID 41555467 · Publisher ↗
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Pharmacokinetics and safety of a telmisartan/amlodipine/rosuvastatin fixed-dose combination tablet compared to co-administration of telmisartan/amlodipine and rosuvastatin in healthy Korean male volunteers.
Moon SJ, Park JS, Kwak YG … +1 more , Kim MG
Int J Clin Pharmacol Ther · 2026 Mar · PMID 41553169 · Publisher ↗
OBJECTIVE: This study was conducted to compare the single-dose pharmacokinetic and safety profiles of JLP-1401 (fixed-dose combination (FDC) of telmisartan/amlodipine/rosuvastatin) to those of each constituent co-adminis...
OBJECTIVE: This study was conducted to compare the single-dose pharmacokinetic and safety profiles of JLP-1401 (fixed-dose combination (FDC) of telmisartan/amlodipine/rosuvastatin) to those of each constituent co-administered in healthy Korean male volunteers. MATERIALS AND METHODS: A total of 40 healthy Korean subjects participated in an open-label, randomized, single-dose, 4-period crossover study. During each treatment period, the subjects received the test drug (FDC tablet of telmisartan/amlodipine/rosuvastatin 80 mg/10 mg/20 mg) or reference drug (co-administration of telmisartan/amlodipine FDC tablet and rosuvastatin tablet). Plasma samples were collected pre dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post dose to evaluate pharmacokinetic profiles. Safety was assessed by the evaluation of adverse events (AEs), laboratory assessments, 12-lead electrocardiograms, physical examinations, and vital sign measurements. RESULTS: The geometric least-square mean ratios and their 90% confidence intervals of AUC and C were 1.01 (0.94 - 1.07) and 0.83 (0.72 - 0.95) for telmisartan, 1.01 (0.99 - 1.04) and 1.03 (1.01 - 1.06) for amlodipine, and 1.03 (0.98 - 1.08) and 0.94 (0.85 - 1.04) for rosuvastatin, respectively. All AEs were of mild or moderate intensity, and there were no significant differences in the incidence of AEs between the treatments. DISCUSSION AND CONCLUSION: The pharmacokinetic profiles of the test and reference drugs were within the bioequivalent criteria, and both drugs were safe and well tolerated.
Pharmacokinetics of the potassium-competitive acid blocker tegoprazan administered by the oral route in healthy Mexicans.
Carrasco-Portugal MDC, González-Hernández GV, López-Cartagena PD … +1 more , Flores-Murrieta FJ
Int J Clin Pharmacol Ther · 2026 Mar · PMID 41553168 · Publisher ↗
BACKGROUND: Tegoprazan is a potassium channel inhibitor with an anti-acid secretion effect. It is metabolized by CYP3A4, a cytochrome enzyme the occurrence of which in the Mexican population, differs from that in some ot...
BACKGROUND: Tegoprazan is a potassium channel inhibitor with an anti-acid secretion effect. It is metabolized by CYP3A4, a cytochrome enzyme the occurrence of which in the Mexican population, differs from that in some other populations. Since the efficacy and safety studies on tegoprazan have been conducted in Koreans, it is of considerable clinical importance to establish whether differences exist in CYP3A4 metabolism between the two populations. AIMS: To evaluate the oral pharmacokinetics of tegoprazan and to compare the pharmacokinetic data with those reported in the literature for Koreans. MATERIALS AND METHODS: The investigation was carried out in a cohort of 20 healthy Mexican volunteers (11 women and 9 men), who were administered a dose of 50 mg after fasting for at least 10 hours. Blood samples were taken at selected time points over 24 hours, and tegoprazan plasma concentrations measured using high-performance liquid chromatography. Pharmacokinetic parameters were compared to those in Koreans reported in the literature. RESULTS: Tegoprazan is rapidly absorbed from the gastrointestinal tract reaching C at ~ 1 hour post dose (t) and is removed from the circulation with an average half-life of ~ 4 hours. The pharmacokinetic parameters obtained were similar to those obtained in Koreans including elimination half-life, maximum tegoprazan concentrations, and oral bioavailability. DISCUSSION AND CONCLUSION: Since no clinically relevant pharmacokinetic differences were observed in the pharmacokinetics of tegoprazan, a substrate for CYP3A4, between Mexicans and Koreans, it is concluded that the efficacy and safety data for tegoprazan obtained in Koreans will be valid in the Mexican population.
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