Cost-effectiveness of prophylaxis with recombinant vs plasma-derived VWF in severe von Willebrand disease in the United States.

ABSTRACT: We evaluated the cost-effectiveness of prophylaxis with recombinant von Willebrand factor (rVWF) vs with plasma-derived von Willebrand factor (pdVWF) for patients with severe Von Willebrand disease. We found that rVWF is a cost-saving factor replacement compared with pdVWF across all willingness-to-pay thresholds in the United States.

Cost-effectiveness of iptacopan for paroxysmal nocturnal hemoglobinuria.

Iptacopan, a novel oral Factor B inhibitor, recently obtained FDA approval for treating paroxysmal nocturnal hemoglobinuria, a rare blood disorder characterized by persistent complement-mediated hemolytic anemia. The standard-of-care (SOC) has traditionally relied on complement C5 inhibitors eculizumab and ravulizumab, which are limited by persistent anemia from extravascular hemolysis and requirement for intravenous infusion. Recent publication of phase 3 studies in this arena reinforces iptacopan as an effective anti-complement monotherapy compared with SOC. Given ongoing price negotiations and limited literature showing its cost-ineffectiveness in the anti-C5-treated population, we conducted a comprehensive cost-effectiveness analysis of iptacopan monotherapy in anti-C5-treated patients from the societal perspective, as compared to C5 inhibition. The primary outcomes were the incremental net monetary benefit (iNMB) across a lifetime horizon and the cost-effective maximum monthly threshold price of iptacopan monotherapy compared to the SOC. The secondary outcome was time saved for patients and nurses with the utilization of oral iptacopan therapy. Iptacopan monotherapy and SOC accrued 12.6 and 10.8 QALYs at costs of $9.52 million and $13.5 million, respectively. Iptacopan remained cost-saving across extensive sensitivity and all scenario analyses, including alternative parameterization for anemia resolution and aggregated individual-level utilities and transition probability matrix. Across all probabilistic sensitivity analyses, iptacopan therapy was favored over SOC in 100% of 10,000 Monte Carlo iterations. Cost-saving thresholds for iptacopan versus anti-C5 in are ~1.1, 1.4, and 1.4 in Brazil, Japan, and the United States. Iptacopan monotherapy can improve quality-adjusted life expectancy for patients while saving healthcare costs across jurisdictions.

Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Decreasing alloimmunization-specific mortality in sickle cell disease in the United States: Cost-effectiveness of a shared transfusion resource.

Red blood cell alloimmunization and consequent delayed hemolytic transfusion reaction (DHTR) incidence and mortality in patients with sickle cell disease (SCD) are high. A shared transfusion resource has decreased both in other countries, while in the United States cost concerns persist. We conducted a Markov cohort simulation of a birth cohort of alloimmunized patients with SCD to estimate lifetime DHTR incidence, DHTR-specific mortality, quality-adjusted life expectancy (QALE), and costs with the implementation of a shared transfusion resource to identify antibody history versus without (i.e., status quo). We conducted our analysis using a lifetime analytic time horizon and from a United States health system perspective. Implementation of shared transfusion resource projects to decrease cumulative DHTR-specific mortality by 26% for alloimmunized patients with SCD in the United States, relative to the status quo. For an average patient population of 32 000, this intervention would generate a discounted increment of 4000 QALYs at an incremental discounted cost of $0.3 billion, resulting in an incremental cost-effectiveness ratio of $75 600/QALY [95% credible interval $70 200-81 400/QALY]. The results are most sensitive to the baseline lifetime medical expenditure of patients with SCD. Alloantibody data exchange is cost-effective in 100% of 10 000 Monte Carlo simulations. The resource would theoretically need a minimum patient population of 1819 patients or cost no more than $5.29 million annually to be cost-effective. By reducing DHTR-specific mortality, a shared transfusion resource in the United States projects to be a life-saving and cost-effective intervention for patients with SCD in the United States.

Distributional Cost-Effectiveness of Equity-Enhancing Gene Therapy in Sickle Cell Disease in the United States.

BACKGROUND: Gene therapy is a potential cure for sickle cell disease (SCD). Conventional cost-effectiveness analysis (CEA) does not capture the effects of treatments on disparities in SCD, but distributional CEA (DCEA) uses equity weights to incorporate these considerations. OBJECTIVE: To compare gene therapy versus standard of care (SOC) in patients with SCD by using conventional CEA and DCEA. DESIGN: Markov model. DATA SOURCES: Claims data and other published sources. TARGET POPULATION: Birth cohort of patients with SCD. TIME HORIZON: Lifetime. PERSPECTIVE: U.S. health system. INTERVENTION: Gene therapy at age 12 years versus SOC. OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) (in dollars per quality-adjusted life-years [QALYs] gained) and threshold inequality aversion parameter (equity weight). RESULTS OF BASE-CASE ANALYSIS: Gene therapy versus SOC for females yielded 25.5 versus 15.7 (males: 24.4 vs. 15.5) discounted lifetime QALYs at costs of $2.8 million and $1.0 million (males: $2.8 million and $1.2 million), respectively, with an ICER of $176 000 per QALY (full SCD population). The inequality aversion parameter would need to be 0.90 for the full SCD population for gene therapy to be preferred per DCEA standards. RESULTS OF SENSITIVITY ANALYSIS: SOC was favored in 100.0% (females) and 87.1% (males) of 10 000 probabilistic iterations at a willingness-to-pay threshold of $100 000 per QALY. Gene therapy would need to cost less than $1.79 million to meet conventional CEA standards. LIMITATION: Benchmark equity weights (as opposed to SCD-specific weights) were used to interpret DCEA results. CONCLUSION: Gene therapy is cost-ineffective per conventional CEA standards but can be an equitable therapeutic strategy for persons living with SCD in the United States per DCEA standards. PRIMARY FUNDING SOURCE: Yale Bernard G. Forget Scholars Program and Bunker Endowment.

Cost-effectiveness of prophylactic emicizumab versus prophylactic recombinant factor VIII in patients with moderate or mild hemophilia A without inhibitors in the United States.

Prophylactic emicizumab is cost-ineffective in adults with moderate or mild hemophilia A without inhibitors at current pricing. The price of prophylactic emicizumab would need to decrease by >35% to become cost-effective in this patient population.

Cross-cultural comparison of continuous deep sedation for advanced cancer patients in East Asian countries: prospective cohort study.

OBJECTIVE: Cultural, social, and legal factors have been known to affect physicians' practice of continuous deep sedation. There have been few quantitative studies to compare continuous deep sedation practice in Asian countries. We aimed to describe and compare clinical characteristics of continuous deep sedation in Japan, Korea and Taiwan. METHODS: Patients with advanced cancer admitted to participating palliative care units were enrolled from January 2017 to September 2018. We evaluated and compared (i) the prevalence of continuous deep sedation, (ii) the characteristics of sedated and non-sedated groups in each country, and (iii) continuous deep sedation administration patterns among the three countries. RESULTS: A total of 2158 participants were included in our analysis, and 264 received continuous deep sedation. The continuous deep sedation prevalence was 10, 16 and 22% in Japan, Korea and Taiwan, respectively. Delirium was the most frequent target symptom in all countries, along with dyspnoea (in Japan) and psychological symptoms (in Korea). Midazolam was most frequently used in Japan and Taiwan, but not in Korea (P < 0.001). Among the patients receiving continuous deep sedation, the hydration amount on the final day was significantly different, with median volumes of 200, 500 and 0 mL in Japan, Korea and Taiwan, respectively (P < 0.001). In Korea, 33% of the continuous deep sedation administration caused a high degree of physicians' discomfort, but 3% in Japan and 5% in Taiwan (P < 0.001). CONCLUSIONS: Clinical practices of continuous deep sedation and physicians' discomfort related to continuous deep sedation initiation highly varied across countries. We need to develop optimal decision-making models of continuous deep sedation and hydration during continuous deep sedation in each country.

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus.

OBJECTIVE: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1-deficient (Fbln1-/-) mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse (Ptger4-/-) DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively. CONCLUSIONS: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.

Factors influencing spiritual well-being in terminally ill cancer inpatients in Japan.

PURPOSE: Spiritual well-being is very important in patients undergoing palliative care. Although psychosocial factors have been suggested to be associated with spiritual well-being, the relationship between physical signs and spiritual well-being has not been fully elucidated. The aim of this study was to explore diverse factors associated with spiritual well-being among palliative care patients in Japan. METHODS: This study is a secondary analysis of a multicenter prospective cohort study involving patients admitted to palliative care units in Japan. Physicians recorded all data prospectively on a structured sheet designed for the study. The spiritual well-being score was measured using the Integrated Palliative Outcome Scale after patients' death in regard to symptoms over the previous 3 days. We classified each patient into "better" score (0-1) and "worse" score (2-4) groups and examined diverse factors associated with spiritual well-being. RESULTS: Among the 1896 patients enrolled, 1313 were evaluated. In the multivariate analysis, seven variables were significantly associated with "worse" score: worse spiritual well-being on admission (2-4) (p < 0.0001), younger age (< 80) (p = 0.0001), hyperactive delirium over 3 days before death (mild/moderate/severe) (p = 0.0001), expressed wish for hastened death (yes) (p = 0.0006), worse communication among patients and families (Support Team Assessment Schedule score 2-4) (p = 0.0008), pleural effusion (present) (p = 0.037), and marital status (unmarried) (p = 0.0408). CONCLUSION: Recognizing factors associated with spiritual well-being is potentially useful for identifying high-risk groups with lower spiritual well-being at the end of life. Further study is required to investigate factors associated with patient-reported spiritual well-being.

Complexity of desire for hastened death in terminally ill cancer patients: A cluster analysis.

OBJECTIVES: The present study aims were (1) to identify the proportion of terminally ill cancer patients with desire for hastened death (DHD) receiving specialized palliative care, (2) to identify the reasons for DHD, and (3) to classify patients with DHD into some interpretable subgroups. METHODS: Advanced cancer patients admitted to 23 inpatients hospices/palliative care units in 2017 were enrolled. Data were prospectively obtained by the primarily responsible physicians. The presence/absence of DHD and reasons for DHD were recorded. A cluster analysis was performed to identify patterns of subgroups in patients with DHD. RESULTS: Data from 971 patients, whose Richmond Agitation-Sedation Scale score at admission was zero and who died in palliative care units, were analyzed. The average age was 72 years, common primary cancer sites were the gastrointestinal tract (31%) and the liver/biliary ducts/pancreas (19%). A total of 174 patients (18%: 95% confidence interval, 16-20) expressed DHD. Common reasons for DHD were dependency (45%), burden to others (28%), meaninglessness (24%), and inability to engage in pleasant activities (24%). We identified five clusters of patients with DHD: cluster 1 (35%, 61/173): "physical distress," cluster 2 (21%, 37/173): "dependent and burdensome," cluster 3 (19%, 33/173): "hopelessness," cluster 4 (17%, 30/173): "profound fatigue," and cluster 5 (7%, 12/173): "extensive existential suffering." CONCLUSIONS: A considerable number of patients expressed DHD and could be categorized into five subgroups. These findings may contribute to the development of therapeutic strategies.

Antenatal Administration of Betamethasone Contributes to Intimal Thickening of the Rat Ductus Arteriosus.

BACKGROUND: Antenatal betamethasone (BMZ) is a standard therapy for reducing respiratory distress syndrome in preterm infants. Recently, some reports have indicated that BMZ promotes ductus arteriosus (DA) closure. DA closure requires morphological remodeling; that is, intimal thickening (IT) formation; however, the role of BMZ in IT formation has not yet been reported. Methods and Results: First, DNA microarray analysis using smooth muscle cells (SMCs) of rat preterm DA on gestational day 20 (pDASMCs) stimulated with BMZ was performed. Among 58,717 probe sets, ADP-ribosyltransferase 3 (Art3) was markedly increased by BMZ stimulation. Quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed the BMZ-induced increase of Art3 in pDASMCs, but not in aortic SMCs. Immunocytochemistry showed that BMZ stimulation increased lamellipodia formation. BMZ significantly increased total paxillin protein expression and the ratio of phosphorylated to total paxillin. A scratch assay demonstrated that BMZ stimulation promoted pDASMC migration, which was attenuated byArt3-targeted siRNAs transfection. pDASMC proliferation was not promoted by BMZ, which was analyzed by a 5'-bromo-2'-deoxyuridine (BrdU) assay. Whether BMZ increased IT formation in vivo was examined. BMZ or saline was administered intravenously to maternal rats on gestational days 18 and 19, and DA tissues were obtained on gestational day 20. The ratio of IT to tunica media was significantly higher in the BMZ-treated group. CONCLUSIONS: These data suggest that antenatal BMZ administration promotes DA IT through Art3-mediated DASMC migration.

Clinical factors associated with the therapeutic outcome of chemotherapy in very elderly cancer patients.

BACKGROUND: The purpose of this study was to detect background factors that might be associated with the therapeutic and curative outcome of chemotherapy in elderly cancer patients aged over 75 years. METHODS: A retrospective study was conducted for elderly cancer patients aged over 75 years who had received more than 2 courses of chemotherapy at our hospital. We analyzed the relationships between RECIST outcome and background factors, such as age, sex, clinical TNM stage, pre-treatment history, ECOG performance status, serum albumin, and Charlson comorbidity index using logistic regression analysis. RESULTS: A total of 103 cancer patients aged over 75 years were analyzed in this study, including 28 with hematological neoplasia, 36 with gastrointestinal tract cancers, 25 with breast cancers, and 14 with other malignancies originating in various tissues. Seventy-one patients (69.1%) had a positive clinical outcome including RECIST CR (complete response), PR (partial response) and SD (stable disease). Multivariate analysis showed that a high serum albumin level of more than 3.5 g/dl and a Charlson comorbidity index score of less than 2 points were positively correlated with a favorable therapeutic outcome. CONCLUSIONS: The results of the current study suggested that serum albumin level and comorbidity index are the principal clinical factors affecting therapeutic outcomes in elderly cancer patients receiving chemotherapy. In the future, these factors may make chemotherapy adaptations, continuity, and effectiveness easier to predict than GA screening.

Phosphorylation of DEPDC1 at Ser110 is required to maintain centrosome organization during mitosis.

DEPDC1 (DEP domain containing 1) is overexpressed in multiple cancers and is associated with cell cycle progression. In this report, we have investigated the expression, localization, phosphorylation and function of DEPDC1 during mitosis. DEPDC1 has two isoforms (isoform a and isoform b), and both of them are increased in mitosis and degraded once cells exit mitosis. DEPDC1a is localized to the centrosome in metaphase, whereas DEPDC1b is localized to the entire cell cortex during mitosis. DEPDC1a, but not DEPDC1b, was required for the integrity of centrosome and organization of the bipolar spindle. Mass spectrometry and biochemical analyses revealed phosphorylation of DEPDC1 at Ser110. The phosphorylation of Ser110 is essential for localization of DEPDC1a to the centrosome. Consistently, non-phosphorylation mutants of DEPDC1a did not rescue disruption of centrosome organization by depletion of endogenous DEPDC1. Our results show a novel role for DEPDC1 in maintaining centrosome integrity during mitosis for the accurate distribution of chromosomes.

Arginine methylation of ubiquitin-associated protein 2-like is required for the accurate distribution of chromosomes.

Proper bioriented attachment of microtubules and kinetochores is essential for the precise distribution of duplicated chromosomes to each daughter cell. An aberrant kinetochore-microtubule attachment results in chromosome instability, which leads to cellular transformation or apoptosis. In this article, we show that ubiquitin-associated protein 2-like (UBAP2L) is necessary for correct kinetochore-microtubule attachment. Depletion of UBAP2L inhibited chromosome alignment in metaphase and delayed progression to anaphase by activating spindle assembly checkpoint signaling. In addition, UBAP2L knockdown increased side-on attachment of kinetochores along the microtubules and suppressed stable kinetochore fiber formation. A proteomics analysis identified protein arginine methyltransferase (PRMT)1 as a direct interaction partner of UBAP2L. UBAP2L has an arginine- and glycine-rich motif called the RGG/RG or GAR motif in the N terminus. Biochemical analysis confirmed that arginine residues in the RGG/RG motif of UBAP2L were directly methylated by PRMT1. Finally, we demonstrated that the RGG/RG motif of UBAP2L is essential for the proper alignment of chromosomes in metaphase for the accurate distribution of chromosomes. Our results show a possible role for arginine methylation in UBAP2L for the progression of mitosis.

Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.

BACKGROUND: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. METHODS: Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. RESULTS: A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. CONCLUSIONS: The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation.

Protein arginine methylation, which is mediated by a family of protein arginine methyltransferases (PRMTs), is associated with numerous fundamental cellular processes. Accumulating studies have revealed that the expression of multiple PRMTs promotes cancer progression. In this study, we examined the role of PRMT1 in ovarian cancer cells. PRMT1 is expressed in multiple ovarian cancer cells, and the depletion of its expression suppressed colony formation, in vivo proliferation, migration, and invasion. To gain insight into PRMT1-mediated cancer progression, we searched for novel substrates of PRMT1. We found that FAM98A, whose physiological function is unknown, was arginine-methylated by PRMT1. FAM98A is expressed in numerous ovarian cancer cell lines and is important for the malignant characteristics of ovarian cancer cells. Our results indicate the possible role of the PRMT1-FAM98A pathway in cancer progression.

UBE2S is associated with malignant characteristics of breast cancer cells.

Ubiquitination is essential for various biological processes, such as signal transduction, intracellular trafficking, and protein degradation. Accumulating evidence has demonstrated that ubiquitination plays a crucial role in cancer development. In this report, we examine the expression and function of ubiquitin-conjugating enzyme E2S (UBE2S) in breast cancer. Immunohistochemical analysis revealed that UBE2S is highly expressed in breast cancer. The depletion of UBE2S by siRNA induced disruption of the actin cytoskeleton and focal adhesions. Interestingly, phosphorylation of FAK at Tyr397, which is important for the transduction of integrin-mediated signaling, was significantly reduced by UBE2S knockdown. We also show that UBE2S knockdown suppressed the malignant characteristics of breast cancer cells, such as migration, invasion, and anchorage-independent growth. Our results indicate that UBE2S could be a potential target for breast cancer treatment.

Population Pharmacokinetic Modeling of Levetiracetam in Pediatric and Adult Patients With Epilepsy by Using Routinely Monitored Data.

BACKGROUND: Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy. METHODS: Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program. RESULTS: A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mL·min·1.73 m, respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively. CONCLUSIONS: Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.

Surgical Ligation for Patent Ductus Arteriosus in Extremely Premature Infants: Strategy to Reduce their Risk of Neurodevelopmental Impairment.

Surgical ligation for patent ductus arteriosus (PDA) in extremely low birth weight infants (ELBWIs) has been shown a possible association with neurodevelopmental impairment (NDI) because of its invasiveness. However, we have undergone surgical ligation for ELBWIs immediately after cyclooxygenase inhibitor failed to close a hemodynamically significant PDA (hsPDA) to maintain proper systemic circulation. We aimed to determine the effect of surgical ligation for hsPDA on NDI in ELBWIs. In enrolled 71 ELBWIs, the clinical parameters, including the developmental quotient (DQ), were collected and compared among three groups that were divided by closure mode: spontaneous closure (n = 11), cyclooxygenase inhibitor therapy (n = 37) and surgical ligation (n = 23). No significant differences in DQ at the age of 36 months among the three groups were found: Median (interquartile range): 92.0 (31.0), 89.0 (22.0) and 92.0 (24.5), respectively. In a comparison between groups of DQ < 70 (n = 15) and DQ ≥ 70 (n = 56), a significant difference was found in the parameters related to prematurity (p < 0.05 for each): gestational age [23.9 (1.70) vs. 25.4 (2.50) weeks], birth weight [595 (183) vs. 714 (192) g], Apgar score < 5 (1 min) (67% vs. 36%), and laser photocoagulation for retinopathy of prematurity (73% vs. 43%), but there was no significant association with hsPDA. Therefore, we propose that surgical ligation for hsPDA in ELBWIs should be immediately carried out for preventing future neurodevelopmental deterioration if the cyclooxygenase inhibitor failed to close hsPDA.