Clinical Pharmacology & Therapeutics最新文献

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.

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.

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.

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.

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.

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.

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.