Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma.

PURPOSE: A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC). PATIENTS AND METHODS: A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure-response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models. RESULTS: The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 µg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 µg/mL) in CD8+Ki67+ T-cell counts. CONCLUSIONS: Our findings support novel insights into tremelimumab pharmacokinetics and exposure-response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.

Prediction of Neurologically Intact Survival in Cardiac Arrest Patients without Pre-Hospital Return of Spontaneous Circulation: Machine Learning Approach.

Current multimodal approaches for the prognostication of out-of-hospital cardiac arrest (OHCA) are based mainly on the prediction of poor neurological outcomes; however, it is challenging to identify patients expected to have a favorable outcome, especially before the return of spontaneous circulation (ROSC). We developed and validated a machine learning-based system to predict good outcome in OHCA patients before ROSC. This prospective, multicenter, registry-based study analyzed non-traumatic OHCA data collected between October 2015 and June 2017. We used information available before ROSC as predictor variables, and the primary outcome was neurologically intact survival at discharge, defined as cerebral performance category 1 or 2. The developed models' robustness were evaluated and compared with various score metrics to confirm their performance. The model using a voting classifier had the best performance in predicting good neurological outcome (area under the curve = 0.926). We confirmed that the six top-weighted variables predicting neurological outcomes, such as several duration variables after the instant of OHCA and several electrocardiogram variables in the voting classifier model, showed significant differences between the two neurological outcome groups. These findings demonstrate the potential utility of a machine learning model to predict good neurological outcome of OHCA patients before ROSC.

Treatment of internuclear ophthalmoparesis in multiple sclerosis with fampridine: A randomized double-blind, placebo-controlled cross-over trial.

AIM: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). METHODS: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV-VDI) and first-pass amplitude VDI (FPA-VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. RESULTS: Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV-VDI (-17.4%, 95% CI: -22.4%, -12.1%; P < 0.0001) and FPA-VDI (-12.5%, 95% CI: -18.9%, -5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average tmax at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). CONCLUSION: Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.

Characteristics of computed tomography in hemodynamically unstable blunt trauma patients: Experience at a tertiary care center.

Emergent exploratory laparotomy is recommended for hemodynamically unstable blunt trauma patients suspected of having hemoperitoneum. However, given the unreliability of ultrasonography and rapid scan speed of computed tomography (CT), CT might help clinicians provide accurate information even in hemodynamically unstable trauma patients. This observational study aimed to describe the bleeding site and hospital course of severe blunt trauma patients with hemoperitoneum diagnosed by CT scan.We enrolled all consecutive adult blunt trauma patients (≥18 years old) who underwent whole-body CT before operation between February 2012 and October 2016. Patients with hemoperitoneum on CT images were included and categorized into hemodynamically stable and unstable (persistent hypotension despite fluid resuscitation) groups.Among 1723 severe blunt trauma patients, 136 patients with hemoperitoneum were included. Of these, 98 (72.1%) patients had documented intraperitoneal injury, and the liver (60.2%) was most frequently damaged site, followed by spleen (23.5%) and mesentery (23.5%). The rate of intraperitoneal organ injury did not differ between hemodynamically stable (n = 107) and unstable (n = 29) groups (69.2% vs 82.8%, P = .15), while the documented active internal bleeding was high in the unstable group (29.9% vs 69.0%, P < .001). In the unstable group, 14 (48.3%) patients underwent emergent operation, while 3 patients underwent embolization, and the others were treated in a conservative manner.Even in hemodynamically unstable hemoperitoneum patients, 17.2% had no documented intraperitoneal injury and over half of the patients were treated without emergent operation.

Trends in the incidence and outcomes of bicycle-related injury in the emergency department: A nationwide population-based study in South Korea, 2012-2014.

OBJECTIVE: This study aimed to examine trends in the incidence and outcomes of bicycle-related injuries in emergency departments (ED) in South Korea. METHODS: We analysed data from the National Emergency Department Information System database for adult patients (≥20 years) with bicycle-related injuries presenting to EDs in South Korea between January 2012 and December 2014. Riders and bicycle passengers whose injuries were associated with bicycle use were included. Serious outcomes were defined as death at the ED, need for emergency operation, or intensive care unit admission. RESULTS: The number of people who commute to work by bicycle increased by 36% from 205,100 in 2005 to 279,544 in 2015. Of 529,278 traffic-related trauma cases, 58,352 (11.0%) were bicycle-related, which increased from 7,894 (10.2%) in the first half of 2012 to 12,882 (12.2%) in the second half of 2014 (p < 0.001). However, the proportion of serious outcomes decreased from 5.0% to 4.2% during the study period (p < 0.001). Serious outcomes were most frequent in the elderly (65-74 years) and older elderly (≥75 years) groups and decreased for all but the elderly age group from 10.3% to 9.8% (p = 0.204). The helmet use rate increased from 14.2% to 20.3% (p < 0.001) but was the lowest in the older elderly group (3.6%) without change during the study period (from 4.7% to 3.7%, p = 0.656). A lack of helmet use was significantly associated with serious outcomes (odds ratio, 1.811; 95% confidence interval, 1.576-2.082). CONCLUSIONS: Although the incidence of bicycle-related injuries increased, the proportion of serious outcomes decreased, possibly due to increased helmet use. Public education on safety equipment use is required, especially in elderly populations.

Disseminated Intravascular Coagulation in Emergency Department Patients With Primary Postpartum Hemorrhage.

The aim of this study was to evaluate the prevalence of disseminated intravascular coagulation and to determine whether the presence of disseminated intravascular coagulation is associated with major adverse events in patients with primary post-partum hemorrhage (PPH) who present to the emergency department.This retrospective case-control study was conducted in the emergency department of a university-affiliated, tertiary referral center between January 1, 2004 and December 31, 2013. Patients were classified into disseminated intravascular coagulation (disseminated intravascular coagulation score ≥ 5) and non-disseminated intravascular coagulation groups. The two groups were compared in terms of clinical characteristics and the occurrence of major adverse events, defined as massive transfusion (≥ 10 units of packed red blood cells within 24 h of emergency department admission), invasive intervention (uterine artery embolization or emergency hysterectomy), hospital days, ventilator-free days, intensive care unit admission, intensive care unit-free days, and in-hospital mortality.Among 255 patients with primary PPH, 57 patients (22.4%) had overt disseminated intravascular coagulation. The disseminated intravascular coagulation group had significantly lower hemoglobin, hematocrit, platelet counts, and fibrinogen levels than the non-disseminated intravascular coagulation group; in addition, they had higher prothrombin times, and D-dimer levels (P < 0.01). The occurrence of major adverse events was greater in the disseminated intravascular coagulation group than in the non-disseminated intravascular coagulation group (96.5% vs. 44.4%, P < 0.01).In conclusion, disseminated intravascular coagulation was frequently found in combination with primary PPH, and the outcome was worse in these patients than in those without disseminated intravascular coagulation.

An increase in initial shock index is associated with the requirement for massive transfusion in emergency department patients with primary postpartum hemorrhage.

The aim of this study was to determine whether initial shock index (SI) was independently associated with the requirement for massive transfusion (MT) in emergency department (ED) patients with primary postpartum hemorrhage (PPH). A retrospective cohort study of ED patients with primary PPH was performed at a university-affiliated, tertiary referral center between January 2004 and May 2012. Patients were classified to two groups: MT group (patients who received ≥10 U of packed red blood cells within 24 h of ED admission) and non-MT group (patients who received <10 U). Variables of the two groups were compared using univariate and multivariate analyses. A total of 126 patients were included in this study. Of these patients, 26 (20.6%) were included in MT group and 100 (79.4%) in non-MT group. Patients in MT group had significantly lower blood pressure and higher heart rate compared with patients in non-MT group (P < 0.01). Initial SI was significantly higher in MT group than in non-MT group (1.3 vs 0.8, P < 0.01). In multivariate logistic regression analysis, initial SI and heart rate were the only variables associated with the requirement for MT, with an odds ratio of 9.47 (95% confidence interval, 1.75-51.28; P < 0.01) and 1.06 (95% confidence interval, 1.02-1.09; P < 0.01), respectively. In conclusion, initial SI was independently associated with the requirement for MT in ED patients with primary PPH. Routine calculation of initial SI can help clinicians to identify patients who may benefit from timely and appropriate use of MT to improve clinical outcomes.

Value of cardiac troponin I for predicting in-hospital occurrence of hypotension in stable patients with acute pulmonary embolism.

Although cardiac troponin I (cTnI) elevations during acute pulmonary embolism (PE) are predictive of in-hospital death, it is not clear whether cTnI measurements at emergency department (ED) admission are predictive of the occurrence of hypotension. The study subjects included all consecutive patients with acute PE (diagnosed by chest computed tomography angiography) in the ED between January 2006 and December 2011. All underwent cTnI tests at ED admission and were divided into two groups based on the occurrence of hypotension within 24 h. Of 457 stable patients with acute PE who were admitted to the ED during the study period, 301 patients were included. Within 24 h of hospitalization, 27 (9.0%) developed hypotension. The patients who developed hypotension had a significantly higher mean cTnI concentration than did the remaining patients (1.01 vs. 0.14 ng/mL, P < 0.00). They were also more likely to be treated with thrombolytic therapy and had higher 28-day and 6-month mortality rates. Cardiac TnI elevation (>0.05 ng/mL) at ED admission was a strong predictor of the development of hypotension within 24 h (odds ratio, 8.2; 95% confidence interval, 2.6-26.1; P = 0.00). The sensitivity, specificity, positive predictive value, and negative predictive value of elevated cTnI were 85%, 66%, 20%, and 98%, respectively. This study suggests that a normal cTnI nearly rules out subsequent development of hypotension within 24 h. This may help to select those patients who would benefit most from intensive clinical surveillance and escalated treatment.

On carbon dioxide storage based on biomineralization strategies.

This study focuses on the separation and storage of the global warming greenhouse gas CO(2), and the use of natural biocatalysts in the development of technologies to improve CO(2) storage rates and provide new methods for CO(2) capture. Carbonic anhydrase (CA) has recently been used as a biocatalyst to sequester CO(2) through the conversion of CO(2) to HCO(-) in the mineralization of CaCO(3). Biomimetic CaCO(3) mineralization for carbon capture and storage offers potential as a stable CO(2) capture technology. In this report, we review recent developments in this field and assess disadvantages and improvements in the use of CA in industrial applications. We discuss the contribution that understanding of mechanisms of CO(2) conversion to CO(3)(-) in the formation and regeneration of bivalve shells will make to developments in biomimetic CO(2) storage.

Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers.

BACKGROUND: Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. METHODS: Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. RESULTS: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone. CONCLUSION: OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.

Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers.

OBJECTIVE: Our objective was to investigate the effect of the uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers. METHODS: Twenty-four healthy subjects were enrolled and grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and pharmacodynamic profiles of intravenous lorazepam were characterized before and after inhibition with 600 mg valproate once daily for 4 days and after induction with rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 10 days between. The plasma concentrations of lorazepam and lorazepam glucuronide were analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after lorazepam administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments and psychomotor coordination tests were administered before and up to 12 hours after drug administration. RESULTS: The UGT2B15*2/*2 group showed 0.58-fold (95% confidence interval, 0.43-0.72; P < .0001) lower systemic clearance during the basal state and 1.37-fold (95% confidence interval, 1.05-1.88; P = .037) higher area under the visual analog scale-time curve during the induced state compared with the UGT2B15*1/*1 group. The mean systemic clearance of lorazepam decreased by 20% in the inhibited state and increased by 140% in the induced state. During the inhibited or induced state, absolute values of clearance were consistently lower in the *2/*2 group, but the percent changes from baseline did not differ significantly by genotype. CONCLUSIONS: Our results suggest that the UGT2B15*2 polymorphism is a major determinant of interindividual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam.