Population pharmacokinetics of high‐dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Objective: This study aimed to develop a population pharmacokinetic model for high‐dose methotrexate (MTX), specifically focusing on the drug urinary excretion process. Methods and results: Three hundred and forty‐eight serum samples and 416 urine samples from 51 Japanese adult patients with malignancies were concurrently fitted into a multi‐compartment model using the nonmem program. In the final model, creatinine clearance (CCR, mL/min) and the MTX dose (DOSE10G; 0 when <10 g, 1 when ≥10 g) were the most significant factors that affected the renal clearance (CL_r) and non‐renal clearance (CL_nr), respectively: CL_r(L/h) = 5·57 × (CCR/80·0)^0·112, V₁(L) = 26·9, Q(L/h) = 0·0778, V₂(L) = 2·27, CL_nr(L/h) = 0·567 × 3·39^DOSE10G, where V₁ and V₂ are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the inter‐compartmental (central–peripheral) clearance. For another nine patients, the model enabled a satisfactory Bayesian estimation using two time‐point serum concentrations. Conclusion: The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high‐dose MTX to predict and control toxic events.     

The microarray identification circular RNA hsa_circ_0105015 up‐regulated involving inflammation pathway in essential hypertension

BackgroundEssential hypertension (EH) is an inflammatory disease, and endothelial dysfunction induced by chronic inflammation is one of the pathogeneses of EH. The expression of some inflammatory mediators may be regulated by the interaction of circular RNAs (circRNAs) and microRNAs (miRNAs).MethodsAn Agilent human circRNA microarray was used to identify the expression profile of circRNAs in EH. qRT‐PCR was used to evaluate the relative expression of circRNAs in 48 pairs of human whole blood samples (sex and age ± 3 years matched) and endothelial cells. TNF‐α was applied to induce endothelial cells inflammation. CircRNA‐miRNA network was predicted by MiRanda software.ResultsThere were 287 circRNAs differentially expressed in the microarray. The top 10 up‐regulated circRNAs in the EH group were hsa_circ_0014243, hsa_circ_0133228, hsa‐circRNA14116‐3, hsa_circ_0079536, hsa‐circRNA13649‐1, hsa_circ_0117886, hsa_circ_0007075, hsa‐circRNA15285‐1, hsa‐circRNA10088‐9, and hsa‐circRNA14119‐10; the top 10 down‐regulated circRNAs were hsa_circ_0100094, hsa_circ_0127342, hsa_circ_0093773, hsa_circ_0096334, hsa_circ_0131618, hsa_circ_0063886, hsa_circ_0097804, hsa_circ_0126640, hsa‐circRNA8935‐1, and hsa_circ_0039978 (fold change in descending order). Hsa_circ_0105015 has two predicted binding sites with hsa‐miR‐637. The relative expression of hsa_circ_0105015 in EH patients was significantly higher than healthy controls (P = .002), and similar results appeared in TNF‐α‐induced endothelial cells. The area under the curve after hsa_circ_0105015 combined with hsa‐miR‐637 was 0.703, P < .001.ConclusionHyperexpression of hsa_circ_0105015 is a significant risk factor of EH and its association with EH involves inflammatory pathways. Hyperexpression of hsa_circ_0105015 combined with hypoexpression of hsa‐miR‐637 indicates vascular inflammation or endothelial dysfunction and has potential as a biomarker for early diagnosis of EH.     

Neurological manifestations in patients with COVID‐19: A systematic review and meta‐analysis

IntroductionThe intensification of coronavirus disease 2019 (COVID‐19) complications, severe symptoms, and high mortality rate has led researchers to focus on this significant issue. While respiratory and cardiac complications have been described as high‐risk manifestations in patients with COVID‐19, neurological complications can also enhance mortality. This study aimed to evaluate the prevalence of neurological complications arises from SARS‐CoV‐2 and assess the mortality rate from neurological complications.Material and MethodsLiterature review was conducted by searching in PubMed/Medline, Web of Sciences, and Embase. After performing search strategies with relevant terms, a number of articles were excluded, including review articles, systematic review or meta‐analysis, duplicate publication of same researchers, congress abstracts, animal studies, case reports, case series, and articles reporting a history of neurological features prior to COVID‐19 infection. After retrieving the data, statistical analysis was performed using the STATA Version 14 software.ResultsFrom 4455 retrieved publications, 20 articles were selected for further analysis. Among 18,258 included patients, 2791 showed neurological symptoms, which were classified into different groups. Headache, confusion, and fatigue were reported as the most non‐specific neurological features in confirmed COVID‐19 patients. Psychiatric symptoms, CNS disorders, cerebrovascular disorders, CNS inflammatory disorders, PNS disorders, neuromuscular disorders, etc., were defined as specific neurological manifestations. The pooled prevalence of neurological manifestations and mortality rate of COVID‐19 patients with neurological features were estimated to be 23.0% (95% CI: 17.8–29.2) and 29.1% (95% CI: 20.3–39.8), respectively.ConclusionNeurological manifestations may commonly happen in patients with COVID‐19. This study reported a high prevalence of neurological complications and mortality rates in COVID‐19 patients. Therefore, patients with COVID‐19 who indicated neurological symptoms should be taken seriously and should receive early treatment to prevent undesirable events.     

Erythropoiesis‐stimulating agents and incident malignancy in chronic kidney and end‐stage renal disease: A population‐based study

Research investigating incident malignancy risk in erythropoiesis‐stimulating agent (ESA) users with chronic kidney disease (CKD) is lacking. We aimed to compare the incident cancer risk between ESA and non‐ESA users with CKD or end‐stage renal disease (ESRD). In this retrospective cohort study, all adults newly diagnosed with CKD or ESRD between 2000 and 2012 were enrolled. The study population included 98,748 patients. After case–control matching, 7115 patients were included. The defined daily dose (DDD) of ESA was used as the unit for measuring the amount of ESA prescribed. The primary outcome was the risk of incident malignancy. The secondary outcomes were incident malignancy risk in different tertiles of cumulative ESA doses and the risk of different types of cancers. The risk of incident malignancy was 1.84 times higher with ESA treatment than without ESA treatment (hazard ratio, 1.84; 95% confidence interval, 1.43–2.36; p < 0.001). The malignancy risk was positively correlated with the cumulative dose of ESA (p‐for‐trend = 0.001) and a significant difference in the high annual cumulative DDD cohort (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.76–3.25; p < 0.001). The risk of genitourinary malignancy was 12.55 times higher with ESA treatment than without ESA treatment (HR, 12.55; 95% CI, 5.78–27.24; p < 0.001). ESA usage is associated with an increased risk of malignancy, particularly genitourinary cancers, in patients with CKD or ESRD. Clinicians should be aware of the occurrence of malignancy, and keep ESA dosage as low as possible.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Erythropoiesis‐stimulating agents (ESAs) are known to impact the outcomes of pre‐existing cancer.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The de novo cancer risk for users of ESAs has not been fully examined. We aimed to compare the incident cancer risk between ESA and non‐ESA users with chronic kidney disease (CKD) or end‐stage renal disease (ESRD).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Users of erythropoiesis‐stimulating agents had 1.84 times increasing risk of overall de novo cancer, and a 12‐fold risk of genitourinary tract cancer. The risk of overall de novo cancer increased proportionally with the dosage of ESAs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Clinicians should more aggressively taper the dosage of ESAs while achieving the target hemoglobin level. Patients with CKD or ESRD treated with ESAs should be more alert to occurrence of malignancies, particularly genitourinary tract cancers.     

Association of tumor necrosis factor alpha ‐308 single nucleotide polymorphism with SARS CoV‐2 infection in an Iraqi Kurdish population

Uncovering risk factors playing roles in the severity of Coronavirus disease 2019 (Covid‐19) are important for understanding pathoimmunology of the disease caused by severe acute respiratory syndrome Coronavirus 2 (SARS CoV‐2). Genetic variations in innate immune genes have been found to be associated with Covid‐19 infections. A single‐nucleotide polymorphism (SNP) in a promoter region of tumor necrosis factor alpha (TNF‐α) gene, TNF‐α −308G>A, increases expression of TNF‐α protein against infectious diseases leading to immune dysregulations and organ damage. This study aims to discover associations between TNF‐α −308G>A SNP and Covid‐19 infection. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used for genotyping a general Kurdish population and Covid‐19 patients. The homozygous mutant (AA) genotype was found to be rare in the current studied population. Interestingly, the heterozygous (GA) genotype was significantly (p value = 0.0342) higher in the Covid‐19 patients than the general population. This suggests that TNF‐α −308G>A SNP might be associated with Covid‐19 infections. Further studies with larger sample sizes focusing on different ethnic populations are recommended.     

Heterogeneous validity of daily data on symptoms of seasonal allergic rhinitis recorded by patients using the e‐diary AllergyMonitor®

BackgroundPatient‐generated symptom and medication scores are essential for diagnostic and therapeutic decisions in seasonal allergic rhinitis (SAR). Previous studies have shown solid consistencies between different scores at population level in real‐life data and trials. For clinicians, the evaluation of individual data quality over time is essential to decide whether to rely on these data in clinical decision‐making.ObjectiveTo analyze the consistency of different symptom (SS) and symptom medication scores (SMSs) at individual level in two study cohorts with different characteristics and explore individual patient trajectories over time.MethodsWithin the pilot phase of the @IT.2020 project on diagnostic synergy of mobile health and molecular IgE assessment in patients with SAR, we analyzed data of 101 children and 93 adults with SAR and instructed them to record their symptoms and medication intake daily via the mobile app AllergyMonitor®. We then assessed the correlation between different SMS and a visual analogue scale (VAS) on the impact of allergy symptoms on daily life at population and individual level.ResultsAt population level, the Rhinoconjunctivitis total symptom score (RTSS) correlated better with VAS than the combined symptom and medication score (CSMS). At individual level, consistency among RTSS and VAS was highly heterogeneous and unrelated to disease severity or adherence to recording. Similar heterogeneity was observed for CSMS and VAS.ConclusionsThe correlation of clinical information provided by different disease severity scores based on data collected via electronic diaries (e‐diaries), is sufficient at population level, but broadly heterogeneous for individual patients. Consistency of the recorded data must be examined for each patient before remotely collected information is used for clinical decision making.     

Follow‐up of 25 patients with treatable ataxia: A comprehensive case series study

Autosomal recessive cerebellar ataxias are a group of heterogeneous early‐onset progressive disorders that some of them are treatable. We performed a 4‐year follow‐up for 25 patients who had treatable ataxia. According to our study, patients would benefit from early detection of treatable ataxia, close observation, and follow‐up.     

High‐flux hemodialysis after administering high‐dose methotrexate in a patient with posttransplant lymphoproliferative disease and impaired renal function

A young patient develops cerebral posttransplant lymphoproliferative disorder. Despite concurrent significantly impaired transplant kidney function use of add‐on high‐flux hemodialysis for additional clearance made the administration of high‐dose methotrexate feasible in this patient without occurence of acute chronic kidney failure and significant hematological toxicity.     

The effect of A1298c polymorphism of the MTHFR gene on anti‐Müllerian hormone levels: experimental and Web‐based analysis

BackgroundThe 5,10‐methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, which is expressed in human oocytes and preimplantation. Due to the involvement of MTHFR in female reproduction, we tend to evaluate the influence of MTHFR A1298C polymorphism on ovarian marker reserves such as serum anti‐Müllerian hormone (AMH) levels in women after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodsA total of 100 women, who underwent ART treatment due to male factor infertility, were recruited into this study. MTHFR A1298C polymorphism was detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) technique, and serum AMH concentrations were measured by an ultrasensitive enzyme‐linked immunosorbent assay (ELISA).ResultsWomen with the CC genotype had higher AMH levels (4.15 ± 1.67 ng/ml), albeit not significant, than carriers with other genotypes after ovarian stimulation. No significant differences existed in terms of miscarriage and live birth rates among different genotype groups.ConclusionThe presence of the C mutant allele of the 1298 polymorphism in the MTHFR gene led to an increasing trend in serum AMH concentrations; however, the numbers of oocytes retrieved decreased in women with mutated genotypes. The influence of the MTHFR C677T polymorphism on embryo quality and pregnancy rate after ART cycles remains unclear.     

Urinary bladder cavernous hemangioma in a 3‐year‐old: A rare case report

Cavernous hemangioma (CH) of urinary bladder occurs relatively infrequently, accounting for 0.6% of all bladder tumors. This tumor may occur sporadically or coexist with other benign and malignant vascular lesions. In this report, we present a rare case of CH in a 3‐year‐old Ugandan girl. A 3‐year‐old girl was referred to Mbarara Regional Referral Hospital (MRRH) for urological evaluation following a 3‐year history of intravaginal swelling, dysuria, and heavy hematuria resulting in anemia. Imaging was consistent with polypoid bladder mass arising from the bladder trigone. Embryonal rhabdomyosarcoma was suspected based on clinical eyeballing. She was worked up for chemotherapy and received 26 cycles of vincristine sulfate, actinomycin‐d, and cyclophosphamide (VAC). Biopsy and fulguration were performed after optimizing the patient. Histopathology confirmed CH. The surgery was uneventful and resulted in complete cure. CH should be considered in the differential diagnosis of childhood genitourinary masses. It is a rare entity in the real‐life clinical practice and therefore can be overlooked. Excision biopsy and histology should be performed before initiating the patients to chemotherapy. CH is very insensitive to chemotherapy and therefore surgery maybe adequate in resource‐limited settings.     

Late potentials and QT dispersion after high‐dose chemotherapy in patients with non‐Hodgkin lymphoma

The most common cardiotoxic effects of high‐dose cyclophosphamide (CY) are electrocardiographic changes and transient arrhythmias. Therefore, we prospectively assessed serial electrocardiogram (ECG) and signal‐averaged electrocardiogram (SAECG) recordings in 30 adult patients with non‐Hodgkin lymphoma (NHL) receiving high‐dose CY as part of high‐dose chemotherapy (HDT) regimen. All patients were treated with anthracyclines earlier. Heart‐rate‐corrected QT interval and QT dispersion (QTc and QTc dispersion) were measured from ECG. QRS duration and late potentials (LPs) were analysed from SAECG. Both ECG and SAECG were recorded 1 day (d) prior to HDT (d?7) at baseline, and 1 day (d?2), 7 days (d+7), 12 days (+12) and 3 months (m+3) after HDT. Stem cells were infused on day 0 (d0). Cardiac systolic and diastolic function were assessed on (d?7), (d+12) and (m+3) by radionuclide ventriculography. At baseline, four patients presented with LPs. Cardiac systolic function decreased significantly (53 ± 2; 49 ± 2%, P = 0·009 versus baseline), whilst no patient developed acute heart failure. QRS duration prolonged and RMS₄₀ reduced significantly versus baseline (104 ± 3; 107 ± 3 ms, P = 0·003; 41 ± 4; 38 ± 3 μV, P = 0·03), and six patients (21%) presented with LPs after CY treatment. Both QTc interval and QTc dispersion increased versus baseline (402 ± 5; 423 ± 5 ms, P<0·001; 32 ± 2; 44 ± 3 ms, P = 0·012), and six patients (20%) developed abnormal QT dispersion. In conclusion, high‐dose CY causes subclinical and transient electrical instability reflected by occurrence of LPs as well as increased QTc interval and QT dispersion. Thus, longer follow‐up is required to confirm the meaning of these adverse effects on cardiac function and quality of life.     

Hypersensitivity in the lungs is responsible for acute respiratory failure in COVID‐19 patients: Case series of patients who received high‐dose/short‐term methylprednisolone

BackgroundCOVID‐19 is a highly contagious respiratory disease caused by the SARS‐CoV‐2 virus. Patients with severe disease have a high fatality rate and face a huge medical burden due to the need for invasive mechanical ventilation. Hypoxic respiratory failure is the major cause of death in these patients. There are currently no specific anti‐SARS‐CoV‐2 drugs, and the effect of corticosteroids is still controversial.MethodsThe clinical data of 102 COVID‐19 patients, including 27 patients with severe disease, were analyzed. The serum levels of total IgE and anti‐SARS‐CoV‐2 specific IgE were compared in healthy controls and COVID‐19 patients, changes in the level of anti‐SARS‐CoV‐2 specific IgE and clinical response to methylprednisolone (MP) treatment were analyzed, and the effect of high‐dose/short‐term MP therapy for patients with critical illness and respiratory failure was determined.ResultsCOVID‐19 patients had elevated serum levels of anti‐SARS‐CoV‐2 specific IgE, and patients with severe disease, especially critical illness, had even higher levels. Application of short‐term/high‐dose MP significantly reduced the level of these IgE antibodies and also blocked the progression of hypoxic respiratory failure. Hypoxic respiratory failure in patients with COVID‐19 is related to pulmonary hypersensitivity.ConclusionsHypersensitivity in the lungs is responsible for acute respiratory failure in COVID‐19 patients. Application of high‐dose/short‐term MP appears to be an effective life‐saving method for COVID‐19 patients who have hypoxic respiratory failure.     

Population pharmacokinetics and exposure‐response analyses of teduglutide in adult and pediatric patients with short bowel syndrome

Teduglutide is a recombinant analog of human glucagon‐like peptide‐2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure‐response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged <1 year, 5 patients; 1–11 years, 86 patients; 12–17 years, 8 patients; 18–79 years, 120 patients), and 259 non‐SBS subjects (including healthy volunteers and subjects with renal or liver impairment). A one‐compartment model with first‐order absorption and linear elimination adequately characterized the PKs of teduglutide. In patients with SBS, the apparent clearance (CL/F), volume of distribution (V/F), and elimination half‐life of teduglutide were 16.0 L/h, 33.9 L, and 1.47 h, respectively. CL/F depended on body weight and renal function, and V/F depended on body weight and age. Maximum concentration (C _max) of teduglutide was similar in adult and pediatric patients, and in Japanese and non‐Japanese patients. A time‐ and exposure‐response model dependent on the C _max of teduglutide adequately characterized the reduction in PS over more than 2 years of treatment. Daily dosing of 0.05 mg/kg teduglutide resulted in a maximum reduction in PS of 5.76 L/week. Higher C _max values were associated with a more important reduction in PS over time. Adult and pediatric patients with SBS presented similar PKs and response to teduglutide.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Short bowel syndrome (SBS) is a malabsorption disorder that usually results from surgical resection of bowel but can also occur as a congenital condition. It manifests as a collection of signs and symptoms, such as malabsorption, diarrhea, fluid and electrolyte disturbances, and malnutrition, and patients with SBS may require long‐term parenteral support (PS). Teduglutide is a recombinant analog of naturally occurring human glucagon‐like peptide‐2, approved for the treatment of PS‐dependent patients with SBS in the United States, Canada, and Europe.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What the population pharmacokinetic (PK) properties are of teduglutide and exposure‐response relationship in Japanese and non‐Japanese adult (18–79 years) and pediatric (4 months–17 years) patients with SBS, and how teduglutide exposure is related to the treatment response.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

PK properties and exposure parameters of teduglutide in Japanese adult and pediatric patients with SBS are similar to those observed in non‐Japanese adult and pediatric patients with SBS. Teduglutide clearance is dependent on body weight and renal function, and volume of distribution is dependent on body weight and age. The exposure‐response model shows that higher maximum concentrations of teduglutide are associated with a greater reduction in PS volume over time.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The population PK properties and exposure‐response relationship of teduglutide support the selection of 0.05 mg/kg daily treatment as the effective dose regimen in adult and pediatric patients with SBS.     

Pharmacokinetic equivalence of CT‐P17 to high‐concentration (100 mg/ml) reference adalimumab: A randomized phase I study in healthy subjects

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT‐P17 to United States‐licensed adalimumab (US‐adalimumab) and European Union‐approved adalimumab (EU‐adalimumab). This double‐blind, parallel‐group, phase I trial (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03970824","term_id":"NCT03970824"}}NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT‐P17, US‐adalimumab, or EU‐adalimumab. Primary end points were PK equivalence in terms of: area under the concentration–time curve from time zero to infinity (AUC_0–inf); AUC from time zero to the last quantifiable concentration (AUC_0–last); and maximum serum concentration (C_max). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80–125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT‐P17; 103 US‐adalimumab; 106 EU‐adalimumab), 308 subjects received study drug. AUC_0–inf, AUC_0–last, and C_max were equivalent among CT‐P17, US‐adalimumab, and EU‐adalimumab, because 90% CIs for the ratios of GLSMs were within the 80–125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single‐dose administration of CT‐P17, EU‐adalimumab, and US‐adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Lower‐cost biosimilars of tumor necrosis factor inhibitors, including adalimumab, have increased patient access to biologic therapy. Currently available adalimumab biosimilars are formulated at a concentration of 50 mg/ml. CT‐P17, a proposed adalimumab biosimilar, is under development at a concentration of 100 mg/ml, consistent with the new high‐concentration formulation of reference adalimumab.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I, randomized, double‐blind study aimed to demonstrate pharmacokinetic equivalence of a single dose of CT‐P17 to European Union‐approved adalimumab and United States‐licensed adalimumab in healthy adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single‐dose CT‐P17 was pharmacokinetically equivalent to high‐concentration European Union‐ and United States‐licensed reference adalimumab in healthy subjects, with comparable safety and immunogenicity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

CT‐P17 may facilitate effective adalimumab treatment by requiring fewer injections than the 50 mg/ml formulation for equivalent dosing regimens. It may also benefit patients by reducing discomfort during injection, compared with the older reference adalimumab formulation or existing adalimumab biosimilars that are formulated with citrate‐containing buffers.     

Native right‐sided endocarditis in intravenous drug user: A case report

An increased rate of hospitalizations due to right‐sided infective endocarditis is currently witnessed due to the rapid rise of IV drug use. In this case report, we aim to discuss the long‐term outcome and highlight the various diagnostic approaches and management difficulties that are encountered in these cases.