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.
Background According to the scientific evidence accumulated to date (ie, genetic, epidemiological, preclinical, clinical), the modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in a variety of conditions predisposing patients to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on or potentially replacement therapy to the current standard of care antithrombotic agents. Patients with hepatic impairment may have an increased risk of bleeding when using existing antithrombotic agents and therefore may benefit from drugs with an improved safety profile. Purpose To assess the effect of mild or moderate hepatic impairment on the pharmacokinetic (PK) properties of BMS-177/JNJ-3093. Methods This was a multicenter, open-label, non-randomized, single-dose study. A single 60-mg oral dose of BMS-177/JNJ-3093 was administered to 9 participants with mild hepatic impairment (Child-Pugh class A), 8 participants with moderate hepatic impairment (Child-Pugh class B), and 9 healthy participants with normal hepatic function. Healthy participants were matched to participants with hepatic impairment in each Child-Pugh class with regard to body weight. To assess the effects of hepatic impairment on BMS-177/JNJ-3093 PK, an analysis of variance was performed on the natural log-transformed Cmax, AUC(INF), and AUC(0-T) with hepatic function group as a fixed effect. Results BMS-177/JNJ-3093 was well tolerated when administered as an oral dose of 60 mg in participants with mild or moderate hepatic impairment and healthy participants with normal hepatic function. There were no deaths, serious adverse events (AEs), severe AEs, bleeding AEs, or discontinuations due to an AE reported during the study. The geometric mean ratios (GMRs) (90% CI) comparing mild hepatic impairment to normal hepatic function were 1.180 (0.735, 1.895) and 1.168 (0.725, 1.882) for total BMS-177/JNJ-3093 maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC(INF)), respectively. The GMRs (90% CI) comparing moderate hepatic impairment to normal hepatic function were 1.140 (0.699, 1.857) and 0.996 (0.609, 1.628) for total BMS-177/JNJ-3093 Cmax and AUC(INF), respectively. Overall, levels of activated partial thromboplastin time (aPTT) increased in an exposure-related manner following single oral doses of 60 mg BMS-177/JNJ-3093 in all groups. Conclusion BMS-177/JNJ-3093 was well tolerated in the normal healthy participants and those with mild or moderate hepatic impairment. The observed changes indicate that a dose adjustment in these populations may not be necessary. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC
Background According to scientific evidence, modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically relevant bleeding in a variety of conditions associated with a high risk of thrombotic events. Milvexian (BMS-986177/JNJ-70033093) is an oral small molecule that binds reversibly to and inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the patient population, milvexian is expected to provide benefit to patients as replacement or add on therapy to current guideline-recommended antithrombotic agents which include aspirin and/or clopidogrel. Purpose This DDI study aimed to investigate the safety and to identify possible pharmacokinetic (PK) or pharmacodynamic (PD) interaction of milvexian when co-administered with aspirin and/or clopidogrel. Methods The study consisted of 3 parts, each of which was a single DDI study using a randomized, 3-period, 3-treatment crossover design. Six unique treatment sequences were utilized in the study. Milvexian was placebo controlled and blinded when co-administered with aspirin and clopidogrel (Part 1), with clopidogrel (Part 2), or with aspirin (Part 3). In each case the subjects crossed over to milvexian monotherapy. Subjects were randomly assigned into 1 part of the study only. Results Overall, multiple dose milvexian 200 mg given BID for 5 days with and without dual antiplatelet therapy (clopidogrel given as 300 mg on Day 1 followed by 4 days of 75 mg clopidogrel, and aspirin 325 mg once daily given for 5 days) was safe and well tolerated. There were 8 mild bleeding adverse events (AEs) reported from 5 subjects in various treatment groups; no trend towards increased bleeding potential was observed when milvexian was co-administered with dual antiplatelet therapy or separately with aspirin or clopidogrel. After co-administration of aspirin and clopidogrel with milvexian, peak (Cmax) and total exposure [AUC(TAU)] of milvexian were reduced 17% and 15%, respectively, on Day, 1 but were not changed on Day 5, compared to milvexian administered alone. After co-administration of clopidogrel or aspirin separately with milvexian, peak and total exposures of milvexian were not changed, compared to milvexian administered alone. Exposure-dependent prolongation of activated partial thromboplastin time (aPTT) and reduction of Factor XI clotting activity (FXIc) were observed with milvexian administration. Effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Conclusion This Phase 1 study in healthy adults demonstrated administration of milvexian alone or in combination with aspirin and/or clopidogrel was not associated with a trend towards AE's including bleeding. Milvexian steady-state exposure and PD effects were similar when milvexian was administered alone or in combination with aspirin and/or clopidogrel. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol Myers Squibb and Janssen Pharmaceuticals
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