Clinical Pharmacology & Therapeutics最新文献

Radiolabeled human mass balance studies are crucial for identifying circulating metabolites and understanding drug absorption, excretion, and clearance pathways. Metabolite profiling involves quantifying all drug-related entities, including parent drug and metabolites in plasma and excreta, using extended liquid chromatography methods coupled with detection through scintillation counting, accelerator mass spectrometry, or non-radiolabeled approaches. Given the labor-intensive nature of sample extraction and analysis, we propose a new paradigm that maximizes gathering information through sample pooling strategies. Our proposal introduces sample pooling strategies by integrating both individual and pooled sample schemes, simplifying decisions, and consolidating existing knowledge into a cohesive document. This aligns with the low statistical power typically associated with mass balance studies that dose six to eight subjects. In metabolite profiling, it is common practice to pool samples either from the limited number of subjects participating in a human mass balance study or from different time points of sample collection. This approach improves efficiency while preserving data integrity. Pooling reduces resource constraints and enables the concentration of samples with relatively low radioactivity levels, resulting in higher quality metabolite profiles. Nevertheless, there are situations when analyzing samples from individual subjects or time points may be preferred. This proposal presents guidance and decision trees designed to facilitate informed decisions about sample pooling to maximize data quality of metabolite profiling in human mass balance studies while efficiently managing resources. These recommendations stem from discussions within the mass balance working group of the IQ Consortium.

Hypertension is a known modifiable risk factor for Alzheimer's disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013-12/31/2016), to identify apparent treatment-resistant hypertension (aTRH), and hypertension-control levels (well-controlled hypertension, intermediate-controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD-9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson-Aalen estimator and log-rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234-1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time (P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837-0.956) and fixed-dose combination medications (OR: 0.804, 95% CI: 0.732-0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.

Axatilimab, a monoclonal antibody targeting colony-stimulating factor 1 (CSF-1) receptor, is approved in the US for the treatment of chronic graft-versus-host disease (cGVHD) after failure of ≥2 lines of systemic therapy. In this study, the effects of antidrug antibody (ADA) status on the pharmacokinetics, pharmacodynamics, efficacy, and safety of axatilimab were evaluated. Among the 319 assessable participants, including 276 participants with cGVHD, 109 (34.2%) were treatment-emergent ADA-positive, with ADA onset occurring within the first month of treatment for 60.8% of treatment-induced ADA-positive participants. Among the 93 patients with cGVHD and treatment-emergent ADAs, 47 (50.5%) patients were neutralizing antibody (NAb)-positive, with NAb onset mostly occurring within the first 6 months of treatment. Samples that were ADA-negative were generally associated with higher axatilimab trough concentrations compared with ADA-positive samples, especially at later time points. Changes in CSF-1 based on ADA status were consistent with changes in axatilimab exposure. In contrast, nonclassical monocyte levels were similar regardless of ADA or NAb status, suggesting that immunogenicity did not affect nonclassical monocytic cell concentrations. No differences in overall response, ≥7-point improvement in modified Lee Symptom Scale responses, or duration of response were observed between the different ADA and NAb subgroups. The incidence of safety events was generally consistent across ADA and NAb subgroups. In conclusion, no meaningful differences in pharmacokinetics, pharmacodynamics, efficacy, and safety were observed between subgroups of axatilimab-treated participants with different ADA statuses. These results suggest that the development of ADAs and NAbs should not affect treatment decisions with axatilimab.

We present model-informed selection of the recommended dose for expansion (RDE) of investigational oral ATR inhibitor tuvusertib, by integrating clinical pharmacokinetics (PK), pharmacodynamics (PD), and safety data from DDRiver Solid Tumors 301 trial Part A1 (NCT04170153). A population PK (POPPK) model was developed to characterize PK and hemoglobin (HGB) reduction after multicycle treatment was simulated using a semi-mechanistic, multivariate POPPK/PD model of reticulocyte (RET), red blood cell (RBC), and HGB dynamics. A semi-mechanistic PK-efficacy model characterized concentration-dependent tumor growth inhibition (TGI) in ARID1A mutant xenograft models. The clinical exposure-PD relationship was described for phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) as a biomarker of ATR inhibition. POPPK simulations predict the average steady-state concentrations to exceed phosphorylated checkpoint kinase 1 (pCHK1) IC₉₀ at 100-180 mg once daily (QD) and 180 mg QD 2 weeks (w) on/1w off. Exposure-related PD suggested target engagement of ≥80% at ≥130 mg QD. POPPK/PD modeling showed partial HGB recovery and lower rates of Grade ≥3 anemia after multicycle treatment with 180 mg QD 2w on/1w off vs. 130 mg and 180 mg QD. Lesser HGB reduction was predicted for 100 mg QD vs. higher QD doses. Translational modeling indicated no effect of the one-week dosing break on TGI at 180 mg QD. The analysis supports tuvusertib 180 mg QD 2w on/1w off as the RDE and 100 mg QD as the no-regret dose for clinical evaluation. This example underscores the value of integrated quantitative pharmacology analyses to inform dose selection using a totality of evidence approach.

Polypharmacy is increasingly recognized as a relevant issue in diabetes care, but its prevalence and clinical relevance in individuals with type 1 diabetes remain underexplored. This study aimed to determine the prevalence of polypharmacy and to identify associated clinical and psychological factors. Participants were recruited from a tertiary diabetes outpatient clinic between February 2020 and April 2021. Polypharmacy was defined as the concurrent use of five or more medications, including insulin. Clinical, sensor-based, and psychosocial data were collected. Logistic regression was used to identify variables independently associated with polypharmacy. A total of 484 individuals with type 1 diabetes were included (mean age 51.3 ± 15.9 years; 51.2% male; median diabetes duration 30 [IQR 16-40] years; mean HbA_1c 60.3 ± 11.6 mmol/mol). Polypharmacy was present in 175 (36.2%) participants. Individuals with polypharmacy were more often female, were older, and had longer diabetes duration, higher BMI, higher HbA_1c, more complications, and higher rates of hospital admission. They also were more likely to have impaired awareness of hypoglycemia and reported higher levels of fear of hypoglycemia with no differences in hyperglycemia-related worry or behavior or diabetes-related emotional distress. Polypharmacy affects over one-third of individuals with type 1 diabetes and is associated with poorer health status and a greater hypoglycemia-related burden. Future studies should investigate whether targeted medication review and psychological interventions may alleviate some of the burden in this high-risk group.

This manuscript describes the scope of implementation and impact of a regulatory agency-qualified panel of six urine biomarkers on drug development, the process for which was conducted and funded by the Critical Path Institute, the Foundation for the National Institutes of Health, and the United States Food and Drug Administration. Since 2018, these qualified kidney injury urine biomarkers have been included in early clinical drug development programs. Drug-induced kidney injury has historically contributed to high drug candidate attrition rates, additional animal testing needed due to the limitations of standard clinical laboratory tests in timely nephrotoxicity detection, and unsustainable development program fiscal costs. By illustrating the practical application, case studies from pharmaceutical companies illustrate how FDA-qualified drug-induced kidney injury biomarkers can enhance early detection and enable more sensitive and/or specific monitoring of nephrotoxicity. Moreover, data from completed trials registered on ClinicalTrials.gov show that the use of these non-standard-of-care biomarkers as prespecified safety endpoints has increased since their qualification in 2018.

This study investigated real-world edoxaban concentrations across different dosing regimens, with a specific focus on patients who met the inclusion criteria of low-dose edoxaban for the Elder Care Atrial Fibrillation (ELDERCARE-AF) trial. Patients with atrial fibrillation receiving edoxaban were enrolled to measure trough concentrations. The levels were compared with the expected therapeutic range (12-43 ng/mL) to define low or high concentrations. Data on ischemic stroke and systemic thromboembolism (SSE), and major bleeding, were collected prospectively. In total, 402 patients (77.2 ± 10.6 years; 52.2% men) were included. The SSE incidence was 1.22 (0.56-2.31) per 100 person years and was significantly associated with low edoxaban concentration (aHR, 4.13 [1.08-15.82]). Among patients meeting the ELDERCARE-AF criteria (n = 160), the use of the 15-mg regimen (ELDER-15 mg, n = 46) vs. the 30-mg regimen (ELDER-30 mg, n = 114) (aOR, 7.65 [2.92-20.09]), higher creatinine clearance (CrCL) (aOR, 1.05 [1.01-1.08]) and lower CHA₂DS₂-VA score (aOR, 0.69 [0.51, 0.95]) were significantly associated with low concentrations. In the ELDER-15 mg group, patients with CrCL > 50 mL/min had more than 50% probability of exhibiting low drug concentrations. The incidence of SSE was numerically higher in the ELDER-15 mg group than the ELDER-30 mg group (2.34 [0.06-13.02] vs. 1.55 [0.32-4.52]), while major bleeding rates were similar (4.67 [0.57-16.89] vs. 5.15 [2.47-9.48]). In conclusion, low edoxaban concentrations have been associated with thromboembolic events. Among ELDERCARE-AF-eligible patients, the 15-mg regimen results in underexposure to edoxaban, particularly when the CrCL exceeded 50 mL/min.

Knowledge of the glomerular filtration rate (GFR) is mandatory when dosing renally eliminated drugs such as vancomycin. In clinical practice, different biomarkers and various equations are used to estimate GFR (eGFR), resulting in varying estimates. These variations may be explained by nonrenal factors, such as muscle status or glucocorticoid administration. This study aimed to evaluate the performance of different eGFR equations in terms of accuracy and precision compared to renal vancomycin clearance, including subgroup analyses for nonrenal confounders. We retrospectively analyzed data from 121 adult allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. All patients received vancomycin treatment including trough concentration therapeutic drug monitoring. The eGFR was calculated using eight equations and compared to the renal vancomycin clearance that was calculated using a pharmacokinetic model and served as the reference. Individual muscle status was determined by computed tomography scans. Median renal vancomycin clearance was 49 mL/minute/1.73 m² (range 24-96). All eight eGFR equations overestimated renal vancomycin clearance. The six (partially) creatinine-based equations were significantly less accurate (bias: 24.0-62.8 mL/minute/1.73 m²) than both cystatin C-based equations (bias: 6.3-9.5 mL/minute/1.73 m²). This decreased accuracy for creatinine-based eGFR was more pronounced in patients with reduced muscle status or glucocorticoid medication. All CKD-EPI equations and the Hoek equation were more precise with an IQR of the difference to renal vancomycin clearance ≤22.5 mL/minute/1.73 m² compared to ≥35.5 mL/minute/1.73 m² (Cockcroft-Gault, MDRD). In conclusion, cystatin C-based eGFR equations are preferable to creatinine-based approaches for vancomycin dosing in allo-HSCT patients.

There are no clinically meaningful differences between bio-originators (BO) and their biosimilars (BS) in safety and efficacy. However, differences in pharmaceutical properties, such as volume and excipient, can occur. This study aimed to compare outcomes between patients transitioning from the modernized adalimumab BO (0.4 mL/no citrate) to BS1 (0.8 mL/citrate) and from BS1 to BS2 (0.4 mL/no citrate) and outcomes for new starters. In this retrospective exploratory cohort study of RA, PsA, and axial SpA patients receiving adalimumab, the (adjusted) 12-month drug survival rates were compared between the transition from the modernized BO to BS1 (Cohort 1, 2021) and from BS1 to BS2 (Cohort 2, 2023) in existing users, and for adalimumab-naïve new starters of the originator and BS1 and BS2 (Cohorts 3 to 5). Subanalyses included drug survival separately for inefficacy and intolerability. In existing users, 983 patients transitioned to BS1, 1082 patients to BS2, with 659 patients in both cohorts. Drug survival rates at 12 months were 73% (95% CI: 70-76) and 90% (95% CI: 88-92), respectively (P < 0.001), adjusted hazard rate ratio (HRR) 0.32 (95% CI: 0.26-0.40) in favor of BS2. The HRR for discontinuation due to inefficacy and tolerability were 0.50 (95% CI: 0.37-0.67) and 0.20 (95% CI: 0.14-0.28), respectively, both favoring BS2. In adalimumab-naïve new starters also, better survival for the originator and BS2 were seen compared with BS1. In conclusion, adalimumab BS1 showed a significantly lower drug survival than BS2, primarily due to lower tolerability. These findings suggest that pharmaceutical differences can have an important impact on drug survival.