Biomarkers provide a powerful and dynamic approach to improve our understanding of the mechanisms underlying ocular diseases with applications in diagnosis, disease modulation or for predicting and monitoring of clinical response to treatment. Defined as measurable indicator of normal or pathological processes, biomarker evaluation has been used extensively in drug development within clinical settings to better comprehend effectiveness of treatment in ocular diseases. Biomarkers in the eye have the advantage of access to multiple ocular matrices via minimally invasive methods. Repeat sampling for biomarker assessment has enabled reproducible objective measures of disease process or biological responses to a drug treatment. This review describes the usage of biomarkers with respect to four commonly sampled ocular matrices in clinic: tears, conjunctiva, aqueous humor and vitreous. Issues that affect the evaluation of biomarkers are discussed along with opportunities to leverage biomarkers such that ultimately, they can be used for customized targeted therapy.

Background Patients with hepatic impairment receiving antithrombotic agents metabolized primarily through the liver can be at risk for bleeding. Milvexian (BMS-986177/JNJ-70033093) is a small-molecule, active-site inhibitor of activated Factor XI (FXIa). Modulation of FXI may provide systemic anticoagulation without increased risk of clinically significant bleeding. Objective This open-label study evaluated the effects of mild or moderate hepatic impairment on the pharmacokinetics of milvexian to assess their impact on safety and dosing. Methods Single doses of milvexian 60 mg were administered to participants with mild hepatic impairment (n = 9), moderate hepatic impairment (n = 8), and normal hepatic function (n = 9). Healthy participants were matched to participants with hepatic impairment by body weight, age, and sex. Analysis of variance was performed on natural log-transformed milvexian exposure parameters, with hepatic function group as a fixed effect. Results Single doses of milvexian 60 mg were generally well tolerated, with no serious adverse events (AEs), bleeding AEs, or discontinuations due to AEs. Geometric mean ratios (90% confidence interval) for total milvexian maximum observed plasma concentration and area under the plasma concentration-time curve from time zero extrapolated to infinite time were 1.180 (0.735-1.895) and 1.168 (0.725-1.882), respectively, for mild hepatic impairment versus normal hepatic function and 1.140 (0.699-1.857) and 0.996 (0.609-1.628), respectively, for moderate hepatic impairment versus normal hepatic function. Across groups, milvexian exposure-related increases were observed for activated partial thromboplastin time. Conclusion Milvexian was well tolerated in participants with normal, mildly impaired, and moderately impaired hepatic function. Observed pharmacokinetic changes suggest it is unlikely that dose adjustments will be necessary in patients with mild or moderate hepatic impairment. Clinical Trial RegistrationClinicaltrials.gov identifier: NCT02982707.

The -methyl-d-aspartate receptor coagonist d-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). We tested inhibitors of ASCT1 and ASCT2 for their effects in rodent models of schizophrenia and visual dysfunction, which had previously been shown to be responsive to d-serine. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7-1.4; however, values for L-4OHPG and L-4ClPG were lower. Systemically administered L-4FPG potently reduced amphetamine-induced hyperlocomotion in mice, whereas L-4OHPG was 100-fold less effective and L-4ClPG inactive at the doses tested. L-4FPG and L-4OHPG did not impair visual acuity in naive rats, and acute systemic administration of L-4FPG significantly improved the deficit in contrast sensitivity in blue light-treated rats caused by retinal degeneration. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS.

Objective The aim of this study was to assess the effect of moderate or severe renal impairment on the pharmacokinetic (PK) properties of milvexian. Methods This open-label, parallel-group study assessed the PK, safety, and tolerability of a single oral 60 mg dose of milvexian in participants with normal renal function ( n = 8; estimated glomerular filtration rate [eGFR] ≥ 90 mL/min/1.73 m 2 ) and participants with moderate ( n = 8; eGFR ≥ 30 to ≤ 59 mL/min/1.73 m 2 ) or severe ( n = 8; eGFR < 30 mL/min/1.73 m 2 ) renal impairment. Regression analysis was performed using linear regression of log-transformed PK parameters versus eGFR. Results Milvexian was well tolerated, with no deaths, serious adverse events, or serious bleeding reported. The maximum milvexian concentration ( C max ) was similar for all groups. Based on a regression analysis of milvexian concentration versus eGFR, participants with eGFR values of 30 and 15 mL/min/1.73 m 2 , respectively, had area under the curve (AUC) values that were 41% and 54% greater than in participants with normal renal function. Median time to maximum concentration ( T max ) was similar for the three groups (4.5–5.0 h). The half-life increased for participants with moderate (18.0 h) or severe (17.7 h) renal impairment compared with those with normal renal function (13.8 h). Conclusion A single dose of milvexian 60 mg was safe and well tolerated in participants with normal renal function and moderate or severe renal impairment. There was a similar increase in milvexian exposure between the moderate and severe renal groups. Clinical Trials Registration This study was registered with ClinicalTrials.gov (NCT03196206, first posted 22 June 2017). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01150-1.

BACKGROUND: Venous thromboembolism (VTE) events are tracked in trauma registries and by administrative data sets. Both databases are used to assess outcomes, despite having varying processes for data capture. STUDY DESIGN: This study was performed at an urban, university-based, Level I trauma center from 2004 to 2014. Retrospective review of the trauma registry and the hospital's administrative database was performed querying for all VTEs. Each VTE was then validated through manual chart review. Confirmed events were those with radiographic evidence of VTE by ultrasound, CT, and/or ventilation-perfusion scan. Sensitivity, specificity, and predictive values were calculated and compared between databases. RESULTS: There were 19,353 trauma patients admitted during the study period; 656 VTEs were identified in the registry and 890 were identified via administrative data; 527 potential events were identified by both databases; 129 events were only in registry; and 363 were only found in the administrative database. We confirmed 636 of 656 events in registry (positive predictive value, 97%; 95% CI, 95.6% to 98.3%) vs 815 of 890 events in administrative data (positive predictive value, 91.6%; 95% CI, 89.75% to 93.4%; p < 0.001). Sensitivity was higher for administrative (87.2% vs 68.0%; p < 0.001), as 299 confirmed VTE events were not in the registry. Differences between the 2 databases were diminished when the analysis excluded untreated events and those present on admission. Twenty-three percent of validated deep vein thrombosis events in the registry were upper extremity events. CONCLUSIONS: The trauma registry showed higher specificity and lower sensitivity compared with administrative data. The low false-positive rate of the trauma registry supports its validity in VTE outcomes research. Additional investigation is needed to evaluate the relevance of the variable sensitivity, likely due to definitional differences. Supplementation of trauma registry data with administrative data can strengthen its completeness.