Clinical Pharmacology & Therapeutics最新文献

In the current landscape, regulatory agencies face the challenge of reconciling timely authorizations for novel medicines addressing life-threatening conditions with thorough evaluations of their benefits and risks. This challenge is pronounced with advanced therapy medicinal products (ATMPs), where expedited approval mechanisms and orphan drug designations are often applied, making post-authorization measures a crucial mechanism to address uncertainties. We compared post-authorization measures imposed by the U.S. Food and Drug Administration and the European Medicines Agency on ATMPs approvals, from 2009 to 2023. A systematic extraction of FDA postmarketing requirements (PMRs) and EMA-imposed post-authorization measures (PAMs) from publicly available regulatory documents was conducted. Descriptive analysis focused on post-authorization measure categories, objectives, study designs, and their status and registration rates. A total of 15 ATMPs were approved in both jurisdictions over the study period. For these products, the EMA imposed 53 PAMs (34 Annex II conditions and 19 Specific Obligations), whereas the FDA imposed 27 PMRs. As of December 2023, 15 EMA-imposed PAMs were fulfilled, with no explicit fulfilments indicated for FDA PMRs. Both agencies promoted real-world data use in around half of the imposed PAMs (23 by EMA vs. 15 by FDA), marking regulators' growing recognition of Real-World Evidence for decision-making. This study highlights disparities between imposed PAMs: EMA imposed more PAMs, covering efficacy, safety, and quality aspects, while the FDA required fewer measures focusing on specific safety concerns. These discrepancies primarily reflect distinct regulatory structures and approaches to further post-authorization data collection between the EMA and FDA, rather than disparities in initial benefit/risk assessments.

The intracellular tacrolimus concentration in CD3⁺ T lymphocytes is proposed to be a better representative of the active component of tacrolimus than the whole blood concentration. However, intracellular measurements are complicated. Therefore, the aim of this study was to describe the relationship between intracellular and whole blood tacrolimus concentrations in a population pharmacokinetic model. Twenty-eight de novo kidney transplant recipients, treated with a once-daily oral extended-release tacrolimus formulation, were followed during the first-month post-transplantation. Additional whole blood and intracellular tacrolimus concentrations were measured at day 6 ± 1 (pre-dose, 4 and 8 hours post-dose) and day 14 ± 3 (pre-dose) post-transplantation. Pharmacokinetic analysis was performed using nonlinear mixed effects modeling software (NONMEM). The ratio between intracellular (n = 109) and whole blood (n = 248) concentrations was best described by a two-compartment whole blood model with an additional intracellular compartment without mass transfer from the central compartment. The ratio remained stable over time. Prednisolone dose influenced the absorption rate of tacrolimus, while hemoglobin, CYP3A4*22 allele carrier, and CYP3A5 expresser status were associated with the oral clearance of tacrolimus (P-value < 0.001). Furthermore, the intracellular tacrolimus concentrations were correlated with the intracellular production of interleukin-2 (P-value 0.015). The intracellular tacrolimus concentration can be predicted from a measured whole blood concentration using this model, without the need for repeated intracellular measurements. This knowledge is particularly important when the intracellular concentration is ready to be implemented into clinical practice, to overcome the complexities of cell isolation and analytical methods.

The Pharmacogene Variation Consortium (PharmVar) serves as a global repository providing star (*) allele nomenclature for the polymorphic human CYP4F2 gene. CYP4F2 genetic variation impacts the metabolism of vitamin K, which is associated with warfarin dose requirements, and the metabolism of drugs, such as imatinib or fingolimod, and certain endogenous compounds including vitamin E and eicosanoids. This GeneFocus provides a comprehensive overview and summary of CYP4F2 genetic variation including the characterization of 14 novel star alleles, CYP4F2*4 through *17. A description of how haplotype information cataloged by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) is also provided.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m² Q1W with 400 mg/m² loading dose). An every-2-weeks schedule (500 mg/m² Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non-inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I–III clinical trials in 852 patients with KRAS wild-type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure–tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi-mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration-time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model-based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non-inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non-inferiority in 94% of cases. Taken together, these analyses provide model-based evidence for clinical non-inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.

Burosumab is indicated for treatment of a rare bone disease, X-linked hypophosphatemia (XLH). The aim of this analysis was to evaluate the relationship between a treatment response biomarker and patient-reported outcomes (PROs). Longitudinal data for PROs were obtained from adults with XLH from a phase III study. Individual rich time profiles of the biomarker, serum phosphate were simulated using a prior population pharmacokinetic-pharmacodynamic model to calculate serum phosphate exposure metrics for each 28-day treatment cycle, which were then merged with PROs data. Item response theory parameters were first estimated to map a latent variable, ψ, that is, disability score, relative to baseline. Next, the relationships between serum phosphate exposures and ψ were modeled using a nonlinear mixed-effect (NLME) modeling approach. A combined item response theory–NLME model with average serum phosphate as a predictor of ψ described PROs data well. The model estimates suggested 28%, 31%, and 25% reduction in Western Ontario and McMaster Universities Osteoarthritis Index, brief pain inventory, and brief fatigue inventory scores, respectively, with every unit increase in average serum phosphate from the lower limit of normal (2.5 mg/dL). Additionally, a time effect of ~ 0.08% improvements each week was estimated. The analysis suggested that burosumab treatment-induced improvements in serum phosphate levels are associated with improvements in PROs in adults with X-linked hypophosphatemia. The analyses confirmed the importance of prolonged serum phosphate level correction in adult patients with XLH. These results can be useful to guide the design of further studies and to design treatment optimization strategies.

Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double-blind placebo-controlled cross-over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA-induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA-DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited.