Interdose Interval Research Articles

Risk of carditis among adolescents after extending the interdose intervals of BNT162b2

Previous studies indicate an increased carditis risk among adolescents following the two-dose messenger RNA COVID-19 vaccine. Several jurisdictions have extended the interdose interval between the first and second doses to reduce the risk. However, the effectiveness of such an extension policy remains inconclusive. Using the territory-wide vaccine record-linked electronic health records in Hong Kong, we conducted a nested case–control study from February 23, 2021 to August 15, 2022. Adolescents aged between 12 and 17 who received two-dose BNT162b2 were included for comparing risks between standard interdose interval (21–27 days) versus extended interdose interval ( ≥ 56 days). The carditis cumulative incidence within 28 days following the second dose was calculated. The adjusted odds ratio was estimated from multivariable conditional logistic regression. We identified 49 adolescents with newly diagnosed carditis within 28 days following the second dose. The crude cumulative incidence is 37.41 [95% confidence interval (CI): 27.68–49.46] per million vaccinated adolescents. Compared to the standard interdose interval group, adolescents with an extended interval had a significantly lower risk of carditis [adjusted odds ratio (aOR) 0.34 (95% CI: 0.16–0.73)]. Sensitivity analysis of carditis occurring within 14 days following the second dose yielded a similar estimate [aOR 0.30 (95% CI: 0.13–0.73)]. Extending the interdose interval of the BNT162b2 vaccine from 21 to 27 days to 56 days or longer is associated with 66% lower risk of incident carditis among adolescents. Our findings contribute towards an evidence-based vaccination strategy for a vulnerable population and potentially informs product label updates.

Comparative effectiveness of alternative intervals between first and second doses of the mRNA COVID-19 vaccines

The optimal interval between the first and second doses of COVID-19 mRNA vaccines has not been thoroughly evaluated. Employing a target trial emulation approach, we compared the effectiveness of different interdose intervals among >6 million mRNA vaccine recipients in Georgia, USA, from December 2020 to March 2022. We compared three protocols defined by interdose interval: recommended by the Food and Drug Administration (FDA) (17-25 days for Pfizer-BioNTech; 24-32 days for Moderna), late-but-allowable (26-42 days for Pfizer-BioNTech; 33-49 days for Moderna), and late ( ≥ 43 days for Pfizer-BioNTech; ≥50 days for Moderna). In the short-term, the risk of SARS-CoV-2 infection was lowest under the FDA-recommended protocol. Longer-term, the late-but-allowable protocol resulted in the lowest risk (risk ratio on Day 120 after the first dose administration compared to the FDA-recommended protocol: 0.83 [95% confidence interval: 0.82-0.84]). Here, we showed that delaying the second dose by 1-2 weeks may provide stronger long-term protection.

P966 The intra-patient variability of adalimumab clearance during an intensive sampling study of Crohn’s disease patients receiving maintenance therapy

Abstract Background Lower adalimumab (ADA) clearance (CL) is associated with improved outcomes in Crohn’s disease (CD) and may be a superior pharmacokinetic (PK) measure than ADA concentrations. We compared intra-patient variability in ADA CL and concentrations within a 14-day treatment cycle and across two consecutive cycles under maintenance treatment. Methods In a previous PK study of CD patients receiving maintenance ADA 40mg fortnightly, samples were collected intensively at 3 visits (day 4-6, 7-9, and 13-14 post dose) across 2 consecutive cycles. Available sera from this cohort were subsequently used to measure ADA concentrations (lower limit quantification: <1.6 µg/mL) and antibody to adalimumab (ATA) status using a drug tolerant homogeneous mobility shift assay, and albumin. Apparent ADA CL (L/day) was calculated incorporating these measure parameters in a nonlinear mixed effect model with Bayesian priors (under steady state assumption) with dose and inter-dose interval with ATA and albumin as covariate. Rates of sustained clinical and biochemical remission (Harvey Bradshaw Index (HBI) score consistently <5 and CRP levels consistently <3 mg/L) were estimated for each patient. Longitudinal changes in PK parameters within-and-across cycles were evaluated using intra-patient coefficient of variation and linear mixed effect models. Results Sera was available from 70 study visits in 12 patients (6 males, mean age 36 years). Median ADA concentrations and CL were 8 µg/mL (IQR 6.0-10.4) and 0.374 L/day (IQR 0.29-0.43), respectively, with ATA detected in one patient (#9). Estimated ADA concentrations and CL is presented in the Table. Intra-patient variability in CL was much lower across the two 14-day cycle (9% and 7%, respectively) compared to intra-patient variability in ADA concentration (15% and 13%, respectively). Linear mixed effect models confirmed these findings with no impact of sampling time on CL (intercept=0.46±0.12 L/day; slope estimate=0.002±0.002 L/day; p=0.16) as compared to significant change in ADA concentrations (intercept=10.6±1.2 µg/mL; slope estimate=-0.25±0.03 µg/mL; p<0.01) over inter-dose interval sampling time. Sustained clinical and biochemical remission was achieved in 5/12 patients (42%); none presented with CL >0.8 L/day (a cut-off previously associated with worse outcomes). Of 7 patients without sustained clinical and biochemical remission, two presented with optimal concentrations (> 10 µg/mL), thus suggestive of mechanistic failure, and one developed ATA, lower concentration and higher ADA CL. Conclusion CL is subject to less intra-patient variability than ADA concentrations, supporting its assessment at any time point within a 14-day treatment cycle.

Real-World Data Suggest Effectiveness of Allogeneic Mesenchymal Stromal (MSC-FFM) Cells in Ruxolitinib-Refractory Acute Graft-Versus-Host Disease

Introduction: Acute graft-versus-host disease (aGvHD) remains the leading cause of treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Current first-line treatment of aGvHD is with high-dose corticosteroids, the standard for steroid-refractory aGvHD (SR-aGvHD) is the Janus kinase (JAK) inhibitor ruxolitinib. Outcomes for patients with ruxolitinib-refractory or -intolerant aGvHD (RR-aGvHD) are poor. Thus in a recent real-world study of adult patients with RR-aGvHD (Abedin BJH 2021) median survival was 28 days (21 days for ruxolitinib refractoriness, 50 days for ruxolitinib intolerance), the probability of overall survival (OS) at 6, 12, and 24 months were about 20%, 16%, and 10%, respectively. We assessed real-world outcomes of patients with RR-aGvHD treated with the random-donor allogeneic MSC preparation “MSC-FFM,” available via Hospital Exemption in Germany. Patients: Between December 2017 and February 2023, 156 patients, including 33 children and adolescents (<18 years of age), received MSC-FFM for RR-aGvHD. Thirty-two German sites contributed 139 patients, while the remaining 17 patients came from seven transplant centers in France, Hungary, Norway, Sweden, and Switzerland. The adult cohort (n=123) consisted of 41% females, with an age range of 19 to 79 years (median 55 years). Except for one patient, all had been diagnosed with malignant diseases (missing information, n=3). Among the adult patients with malignant diseases, 88% (n=105) received HSCT for acute myeloid leukemia (AML), advanced myelodysplastic syndrome, myeloproliferative neoplasm or lymphoma, and 12% (n=15) for acute lymphoblastic leukemia (ALL). In the pediatric cohort (n=33), 48% of patients were females, with an age range of 0 to 17 years (median 9 years). Overall, 58% of pediatric patients (n=19) had malignant diseases as the indication for allogeneic HSCT, 42% (n=8) having ALL and 32% (n=6) with AML. The remaining 42% of pediatric patients (n=14) had non-malignant diseases as the indication for HSCT. Of the adult patients, 6 (4.9%) had grade II, 52 (42.3%) had grade III, and 63 (51.2%) had grade IV aGvHD, with no specification reported for 2 patients (1.6%). In children, 2 (6.1%) had grade II, 10 (30.3%) had grade III, and 21 (63.6%) had grade IV Treatment: MSC-FFM is manufactured from pooled bone marrow mononuclear cells from eight HLA-disparate healthy donors. MSCs are selected by plastic adherence, expanded until the end of passage 3, then frozen in saline-albumin with DMSO. The recommended dosing for MSC-FFM is 1-2 million cells/kg body weight (BW), for four weekly doses. The median dose administered was 1.18 million cells/kg BW, with a median number of four doses and a median inter-dose interval of 7 days. Results: Safety: Tolerability of MSC-FFM was good, with only five adverse drug reactions reported in three adult patients (chills, BK virus cystitis, increase in C-reactive protein [reported twice in one patient], nausea) and did not result in cessation of MSC treatment or dose reductions. Response: The overall response rate at day +28 was 49% (95%-CI: 41-58%), with 45% (36-55%) in adults and 64% (45-80%) in children. Most responses were durable, resulting in an overall response rate of 49% (41-57%) for both adults and children at 2 months, and 40% (31-48%) at 6 months. Survival: Overall survival at 6, 12, and 24 months was 47% (38-56%), 35% (27-44%), and 29% (21-38%) for adults, and 59% (40-74%), 42% (24-58%), and 37% (19-54%) for children, respectively (Table 1). Median overall survival was 5.8 months. These outcomes compare favourably to published overall survival estimates for adult RR-aGvHD patients not treated with MSC-FFM (Abedin BJH, see above). Summary: The unique MSC-preparation MSC-FFM appears to be effective against RR-aGvHD.

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

B-060 Measurement of Infliximab Clearance using a Bayesian Forecasting Tool and Impact of Albumin and Immunization Status During Maintenance Treatment of Inflammatory Bowel Disease

Abstract Background Accelerated Clearance of monoclonal antibodies such as Infliximab (IFX) is a known predictive factor of pharmacokinetic origin that associates with poor outcome in patients with Inflammatory bowel diseases (IBD). We have implemented a Bayesian forecasting tool for IFX (PredictrPK® IFX) and calculated its Clearance. Our objective was to evaluate the impact of Albumin (ALB) and antibodies to IFX (ATI) on Clearance and exposure from patient specimens with IBD and submitted for testing in the routine clinical pharmacokinetic laboratory. Methods IFX concentration and ATI status were determined from serum using a homogenous mobility shift assay. Serum ALB concentration was determined using nephelometry. Clearance was estimated using inputted IFX concentration, ATI status, ALB, dose and interdose interval, and nonlinear mixed effect modeling with Bayesian priors. Patient specimens were collected anytime 20 days after the infusion and submitted for testing. Median Clearance (expressed as L/day) and estimated IFX trough concentrations by ATI status and lower Albumin levels (<4.0 g/dL) was calculated. Statistical analysis consisted of nonparametric Mann-Whitney tests. Results The prevalence of ATI was 9.1% in this cohort of patient specimens. Median Clearance was 0.246 L/day (IQR: 0.191–0.323 L/day) and median IFX Trough concentration was 11.9 µg/mL (IQR: 6.5–19.9 µg/mL). ATI status associated with lower IFX Trough concentrations and higher Clearance (P < 0.01). Lower ALB concentration regardless of ATI status also associated with lower IFX Trough concentrations (P < 0.01). There was twofold higher Clearance and twelvefold lower IFX Trough concentration in the presence of ATI and lower ALB. Results are presented in Table 1. Conclusion The data are consistent with the notion that IFX immunization and lower ALB impact Clearance and exposure to IFX.

B-304 Performance of Alternative Proficiency Testing Program for Bayesian Forecasting Tool of Infliximab Exposure in Clinical Pharmacokinetic Laboratory

Abstract Background We have developed a Bayesian (PK) forecasting and dosing tool for Infliximab (IFX), a monoclonal antibody targeting Tumor necrosis factor α. This novel dosing tool employs machine learning and proficiency of the algorithm must be established. Our objective was to implement an alternative proficiency testing program (APT) in the routine clinical (PK) laboratory. Methods The test (PredictrPK® IFX) is validated and measures serum IFX and antibodies to IFX (ATI) concentrations using a homogenous mobility shift assay by size exclusion HPLC and albumin (ALB) by nephelometry. Determinations are inputted with weight, dose, and interdose interval provided on test requisition in the Bayesian forecasting PK tool which uses non-linear mixed effect to calculate the individual parameter estimates, Clearance and predicted trough concentrations. APT is conducted using five previously tested patient samples, blinded to testing personnel and retested in the same manner as the routine method of analysis every six months. APT consists of two components, a component evaluating standalone IFX, ATI, and ALB analytes, and a second component evaluating the Bayesian forecasting PK tool in estimating Clearance and trough concentrations. Criteria for acceptable performance is set at target value ± 20% for standalone analytes and forecasted PK estimates. Acceptable ATP score corresponds to 4/5 samples with passing grade. Results The results from two consecutive APT results with six months intervals is presented in Fig. 1. Comparing the results to the original assayed data at the time of collection, the APT results showed IFX concentration, ATI and ALB within 20% of target value. Clearance and estimated trough concentrations calculated using the Bayesian forecasting tool also met acceptability criteria (100% passing grade). Conclusion We have implemented an APT for Bayesian forecasting tool in the clinical PK laboratory.

Real Life Observational Study of Treatment Success of Monoclonal Antibodies for Refractory Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a mainly type-2-driven inflammatory disease that is often refractory to medical and surgical treatment and characterized by a high rate of recurrence. Monoclonal antibodies have been approved for severe refractory CRSwNP. Randomized controlled trials (RCT) have shown significant improvement in objective and subjective parameters. The results of these RCTs cannot necessarily be transferred to daily routine. The purpose of this retrospective study is to evaluate the treatment effects of biologics in patients with CRSwNP in a real-life setting. Patients treated with one of the approved biologics since July 2020 with at least 6 months follow-up were included in the study. Changes in SNOT-22 and nasal polyp score (NPS), as well as subjective change in sense of smell, number of sinus surgeries prior to and during treatment, comorbidities, discontinuation or change of monoclonal antibody and adverse events were evaluated. Thirty-three patients were included in this study. The mean SNOT-22 score and NPS improved significantly. The subjective assessment of sense of smell showed an improvement in 81.8% of patients. The monoclonal antibody had to be changed in seven patients. No severe adverse events occurred during the initiation of the treatment and follow-up. Biologics can be a treatment option in patients with severe refractory CRSwNP, showing significant improvements in quality of life, symptoms and polyp scores in randomized controlled trials and clinical routine with rare complications. Further research is needed to evaluate possible biomarkers, interdose interval prolongation and long-term safety.

Natalizumab extended-interval dosing in a real-life setting

BackgroundNatalizumab is a high-efficacy therapy for recurrent multiple sclerosis (RMS) with a four-week administration interval. Controlled trials have shown that extending this interval to six weeks led to better safety without increasing the risk of relapse. We aimed to analyze the safety of extending the natalizumab interdose interval from 4 to 6 weeks in a real-life setting. MethodsThis monocentric retrospective self-controlled study included adult patients with RMS treated with natalizumab with a four-week interval between infusions for a minimum of six months, before switching to a six-week interval. The main outcomes were the incidence of MS relapse, new MRI lesions, and MRI activity signs during the two periods, with patients being their own controls. ResultsFifty-seven patients were included in the analysis. The mean (95%CI) annualized relapse rate (AAR) before natalizumab introduction was 1.03 (0.52; 1.55). During the four-week interval dosing period, no patient presented with an MS relapse, and seven (13.5%) patients had new MRI lesions. During the six-week interval dosing period, no relapse was observed and two (3.6%) patients had new MRI lesions. ConclusionWe did not observe more relapses or signs of MRI activity when extending the interval between natalizumab infusions from four to six weeks.

Rat BM-MSCs secretome alone and in combination with stiripentol and ISRIB, ameliorated microglial activation and apoptosis in experimental stroke

BackgroundStroke, a devastating neurological emergency, is the leading cause of worldwide mortality and functional disability. Combining novel neuroprotective drugs offers a way to improve the stroke intervention outcomes. In the present era, the combination therapy has been proposed as a plausible strategy to target multiple mechanisms and enhance the treatment efficacy to rescue stroke induced behavioral abnormalities and neuropathological damage. In the current study, we have investigated the neuroprotective effect of stiripentol (STP) and trans integrated stress response inhibitor (ISRIB) alone and in combination with rat bone marrow derived mesenchymal stem cells (BM-MSCs) secretome in an experimental model of stroke. Materials & MethodsStroke was induced in male Wistar rats (n = 92) by temporary middle cerebral artery occlusion (MCAO). Three investigational agents were selected including STP (350 mg/kg; i.p.), trans ISRIB (2.5 mg/kg; i.p.) and rat BM-MSCs secretome (100 µg/kg; i.v). Treatment was administered at 3 hrs post MCAO, in four doses with a 12 hrs inter-dose interval. Post MCAO, neurological deficits, brain infarct, brain edema, BBB permeability, motor functional and memory deficits were assessed. Molecular parameters: oxidative stress, pro inflammatory cytokines, synaptic protein markers, apoptotic protein markers and histopathological damage were assessed. ResultsSTP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, significantly improved neurological, motor function and memory deficits along with significant reduction in pyknotic neurons in the brain of post MCAO rats. These results were correlating with significant reduction in pro-inflammatory cytokines, microglial activation and apoptotic markers in the brain of drug treated post MCAO rats. ConclusionSTP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, might be considered as potential neuroprotective agents in the acute ischemic stroke (AIS) management.

Myocarditis or Pericarditis Events After BNT162b2 Vaccination in Individuals Aged 12 to 17 Years in Ontario, Canada

The risk of myocarditis or pericarditis after COVID-19 messenger RNA vaccines varies by age and sex, and there is some evidence to suggest increasing risk with shorter intervals between dose 1 and 2 (ie, interdose interval). To estimate the incidence of reported myocarditis or pericarditis after BNT162b2 vaccine among adolescents and to describe the clinical information associated with these events. This was a population-based cohort study using passive vaccine safety surveillance data linked to the provincial COVID-19 vaccine registry. Included in the study were all adolescents aged 12 to 17 years in Ontario, Canada, who received 1 or more doses of BNT162b2 vaccine between December 14, 2020, and November 21, 2021, and reported an episode of myocarditis or pericarditis. Data were analyzed from December 15, 2021, to April 22, 2022. Receipt of BNT162b2 (Comirnaty [Pfizer-BioNTech]) vaccine. Reported incidence of myocarditis or pericarditis meeting level 1 to 3 of the Brighton Collaboration case definition per 100 000 doses of BNT162b2 administered by age group (12-15 years vs 16-17 years), sex, dose number, and interdose interval. All clinical information associated with symptoms, health care usage, diagnostic test results, and treatment at the time of the acute event were summarized. There were approximately 1.65 million doses of BNT162b2 administered and 77 reports of myocarditis or pericarditis among those aged 12 to 17 years, which met the inclusion criteria during the study period. Of the 77 adolescents (mean [SD] age, 15.0 [1.7] years; 63 male individuals [81.8%]), 51 (66.2%) developed myocarditis or pericarditis after dose 2 of BNT162b2. Overall, 74 individuals (96.1%) with an event were assessed in the emergency department, and 34 (44.2%) were hospitalized (median [IQR] length of stay, 1 [1-2] day). The majority of adolescents (57 [74.0%]) were treated with nonsteroidal anti-inflammatory drugs only, and 11 (14.3%) required no treatment. The highest reported incidence was observed among male adolescents aged 16 to 17 years after dose 2 (15.7 per 100 000; 95% CI, 9.7-23.9). Among those aged 16 to 17 years, the reporting rate was highest in those with a short (ie, ≤30 days) interdose interval (21.3 per 100 000; 95% CI, 11.0-37.2). Results of this cohort study suggest that there was variation in the reported incidence of myocarditis or pericarditis after BNT162b2 vaccine among adolescent age groups. However, the risk of these events after vaccination remains very rare and should be considered in relation to the benefits of COVID-19 vaccination.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial β-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial β-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Novel Therapeutic Approaches to Invasive Candidiasis: Considerations for the Clinician.

Invasive candidiasis (IC), due to the yeast pathogen Candida, is still a major cause of in-hospital morbidity and mortality. The limited number of antifungal drug classes and the emergence of multi-resistant Candida species, such as Candida auris and some Candida glabrata isolates, is concerning. However, recent advances in antifungal drug development provide promising perspectives for the therapeutic approach of IC. Notably, three novel antifungal agents, currently in Phase II/III clinical trials, are expected to have an important place for the treatment of IC in the future. Rezafungin is a novel echinocandin with prolonged half-life. Ibrexafungerp and fosmanogepix are two first-in-class antifungal drugs with broad spectrum activity against Candida spp., including C. auris and echinocandin-resistant species. These novel antifungal agents also represent interesting alternative options because of their acceptable oral bioavailability (ibrexafungerp and fosmanogepix) or their large interdose interval (once weekly intravenous administration for rezafungin) for prolonged and/or outpatient treatment of complicated IC. This review discusses the potential place of these novel antifungal drugs for the treatment of IC considering their pharmacologic properties and their preclinical and clinical data.

Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study.

Gradual, hyperbolic tapering has been proposed as a method to reduce the risk of withdrawal effects and potential relapse of an underlying condition by minimising disruption of existing equilibria. We applied hyperbolic tapering principles in silico to long-acting aripiprazole to generate regimens for withdrawal in clinical practice. We derived thresholds for taper rates using existing studies and consensus. Using pharmacokinetic data for aripiprazole long-acting injectable antipsychotic (ALAI), we conducted in silico modelling to examine the impact of abrupt cessation of long-acting injectable antipsychotic (LAI) medication and the effect of prolonging inter-dose interval on plasma aripiprazole levels and consequent D2 occupancy. We also modelled transitions from LAI medication to oral medication. Regimens were designed to afford a rate of reduction between 5 and 12.5 percentage points of D2 occupancy per month. Abrupt discontinuation of ALAI was shown to lead to a maximal D2 occupancy reduction of 16.8 percentage points per month; prolongation of the inter-dose interval of ALAI produced a slower reduction. Specifically, hyperbolic tapering was afforded by prolongation of a 400 mg ALAI inter-dose interval from 4 to 7 weeks, before reducing the dose to 300 mg ALAI. This could then be administered at up to 4-week (for 6% maximal D2 occupancy change), 6-week (9% change) or 7-week (11% change) intervals. Switching to oral medication - 5, 2.5 and 1.25 mg for the three regimens, respectively - is required for ALAI to complete full cessation to prevent too rapid a reduction in D2 occupancy. Oral medication should probably be maintained at a consistent dose for 3-6 months before further reductions to account for residual LAI being concurrently eliminated. Hyperbolic dose tapering is possible with ALAI through prolongation of the inter-dose interval and may reduce the risk of relapse compared to abrupt discontinuation of LAI medication.

Concomitant Use of Sutimlimab and COVID-19 Vaccines in Patients with Cold Agglutinin Disease from the Phase 3 Cardinal and Cadenza Studies

Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, characterized by chronic hemolysis mediated by classical complement pathway activation. The ongoing COVID-19 pandemic has posed an additional challenge in treating patients with CAD. Anti-CD20 therapies (commonly used off-label to treat CAD) increase the risk of serious COVID-19 infection and reduce the immune response to COVID-19 vaccines. Recent evidence has also shown a correlation between CAD exacerbations and both COVID-19 and COVID-19 vaccines; raising concern amongst clinicians as CAD patients are usually elderly with comorbidities and will likely require additional boosters during the ongoing pandemic. Sutimlimab (SUT), recently FDA approved for patients with CAD, is a first-in-class humanized monoclonal antibody which selectively targets C1s in the classical complement pathway; addressing the underlying mechanism of hemolysis in CAD. In the Phase 3 CARDINAL (NCT03347396) and CADENZA (NCT03347422) studies, SUT treatment led to rapid and sustained increases in hemoglobin and clinically meaningful improvements in fatigue and was generally well tolerated - reported adverse events (AE) were consistent with elderly populations. Both studies spanned the period before and during the pandemic; investigators were advised to vaccinate enrolled patients without stopping SUT treatment. However, the impact of SUT on immune response to COVID-19 vaccination is unknown. Objective: To explore concomitant use of COVID-19 vaccines and SUT in patients with CAD Methods: Post-hoc analysis from the open label extension (OLE) part of the CADENZA and CARDINAL studies. COVID-19 cases/diagnoses were collected via the regular AE reporting system. Data on tolerability to COVID-19 vaccine was collected through AE reports. Immunogenicity to COVID-19 vaccines was analyzed in a subset of patients fully vaccinated (2 doses) against COVID-19 and had consented to the use of stored samples (collected no later than 6 months after vaccination). Anti-Sars-CoV-2 Spike (EUROIMMUN Anti-SARS-CoV-2 ELISA) and anti-Sars-CoV-2 Nucleocapsid (Abbott Architect i2000 SR) IgG titers were measured. Three patients who tested positive for COVID-19 during Part A of both studies were excluded from the immunogenicity analysis. Results: Of the 61 completers from both studies, 47 received at least one dose of a COVID-19 vaccine; 14 received none; 11 had an additional booster. All participants, regardless of vaccination status, had similar demographic and clinical characteristics. Among those vaccinated, most (83%) received both doses during the studies; of these, mRNA vaccines were the most common (79%). The mean inter-dose interval for fully vaccinated patients (n=37) was 38 days; those who received 1 booster (n=11) had a mean of 165 days between the last dose and booster. No COVID-19 cases were reported during the OLE. Ten AEs were reported in 8 patients during the 7 days after any vaccine dose, but none more than once, and there were no serious AEs. SUT therapy was postponed/skipped twice due to vaccine administration, at the investigator's discretion. Anemia and hemolysis markers, including hemoglobin and total bilirubin, were measured after vaccination to assess its impact on hemolytic activity. No indications of hemolytic exacerbation were observed (Table 1). The immunogenicity analysis comprised 27 patients. All patients developed an immune response post-vaccination, measured via positive IgG anti-spike antibodies (Figure 1). The mean time between last dose and serum collection was 65 days (range: 25-137). Antibody titers were similar irrespective of gender or age. A further analysis performed on 6 patients with booster vaccinations demonstrated elevated immune responses pre to post booster (mean [95% CI] log10 titer change: 1.82 [0.79-2.85]). To rule out previous asymptomatic COVID-19 infection, anti-nucleocapsid SARS-Cov-2 IgG antibodies were assayed and were negative in all cases. Conclusions: COVID-19 vaccination response was not impaired in patients with CAD being treated with SUT. COVID-19 vaccines were well tolerated, and there were no signs of increased hemolytic marker activity following COVID-19 vaccination in patients receiving SUT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Meropenem Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy.

We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure. Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT>1-4×MIC). A total of 27 patients with a median age of 4 [interquartile range 0-11] years, a median body weight of 16 [range 7-35] kg receiving continuous renal replacement therapy were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (Qeff) produced significant effects on clearance (CL): [Formula: see text] and [Formula: see text], where Vpop and CLpop estimates were 32.5 L and 5.88 L/h, respectively, normalized to a 70-kg BW and median Qeff at 1200 mL/h. Using this final model and Monte Carlo simulations, for patients with Qeff over 1200 mL/h, meropenem continuous infusion was adequate in most cases to attain 100% fT>1-4xMIC. For bacterial infections with a low minimum inhibitory concentration (≤2 mg/L), meropenem intermitent administration was appropriate for patients weighing more than 20 kg with Qeff <500 mL/h and for patients weighing more than 10 kg with Qeff <100 mL/h. Meropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

S725 linical Utility of Precision-Guided Dosing Tool for Infliximab During Maintenance Therapy of Inflammatory Bowel Disease

Introduction: A precision-guided dosing tool that uses Bayesian data assimilation was developed to forecast Infliximab (IFX) exposure. Our objective was to establish the utility of the tool in clinical decision making during IFX maintenance therapy when used reactively, to address inadequate disease control that results from suboptimal exposure, and proactively, to sustain exposure commensurate with disease remission in inflammatory bowel disease (IBD). Methods: Blood specimens were collected, anytime beyond 20 days after a prior infusion in a prospective study (EMPOWER). Pharmacokinetic (PK) testing was conducted at Prometheus Laboratories (San Diego, CA). Serum IFX, antibodies to IFX (ATI) and albumin concentrations were all imputed with dosing regimen and weight in a Bayesian data assimilation tool to produce individualized PK profiles that forecasted IFX concentration and time to trough concentration below pre-specified thresholds (e.g., < 10 µg/mL). Forecasted exposure at various dosing regimens was also provided. Physician’s global assessment of disease activity was collected with the decision to change IFX dosing that resulted from PK test results. Statistical analysis consisted of Mann-Whitney and Fisher Exact test as appropriate. Results: A total of 111 patients were assessed by 21 physicians. A change in IFX dose regimen was initiated in 51 patients (46%). Inadequate exposure and forecasted IFX levels below 10 µg/mL associated with dose intensification (76%, median IFX 6.3 µg/mL) (p< 0.01), with lower remission rate (23.5%) achieved in that group as compared to two other groups having better disease control and PK profiles (p< 0.001) (Table). Forecasted IFX levels below 10 µg/mL were associated with 4-fold higher likelihood of active disease (OR=4.1; 95%CI: 1.7-9.4) as compared to IFX levels above 10 µg/mL (p< 0.01). Time to trough below 10µg/mL was shorter in active disease (median: 46 days, IQR: 32-59) than in remission (median 57 days, IQR: 48-69) (p< 0.001). As presented in Figure, dose intensification using a 5 mg/kg every 4 weeks dosing regimen forecasted 2.3-fold higher IFX levels as compared to a 10 mg/kg every 8 weeks dosing regimen (median of 17.1 vs 7.4 µg/mL, respectively) (p< 0.001). Similar results were observed among patients presenting with disease remission. Conclusion: Our study suggests that the precision-guided dosing tool provides clinical utility and helps with dose adjustments in both interval changes as well as dose intensification.Figure 1.: Forecasted IFX Exposure at various dose and interdose intervals, given the individual PK parameters Table 1. - Patient Characteristics (n=111), by treatment intervention based on test results Variable IFX Dose RegimenReductionN=17 IFX Dose RegimenContinuationN=60 IFX Dose RegimenIntensificationN=34 OverallPopulationN=111 Patient Characteristics Age (years) 16 (14-19) 32 (18-45) 32 (17-46) 26 (16-44) Female (%, n/N) 44.1% (7/17) 43.3% (26/60) 44.1% (15/34) 43.2% (48/111) CD/UC/Indeterminate 13/3/1 36/15/8 22/9/3 71/27/12 Weight (Kg) 64 (43-76) 71 (61-92) 69 (61-92) 70 (60-84) Dose mg/Kg 10.0 (9.0-10.4) 8.2 (5.0-10.0) 5.5 (5.0-10.0) 8.0 (5.1-10.0) Interdose interval (weeks) 6 (5-8) 8 (6-8) 8 (6-8) 8 (6-8) PGA Remission Status, remission (%, n/N) 70.6% (12/17) 41.7% (25/60) 23.5% (8/34) 40.5% (45/111) Clinical PK Measurements Measured IFX levels (µg/mL) 23.3 (17.2-28.5) 12.9 (7.2-20.6) 8.0 (5.2-14.7) 12.5 (7.2-20.9) ATI status (%, n/N) 0% (0/17) 10.0% (6/60) 11.8% (4/34) 9.0% (10/111) Albumin (g/dL) 4.1 (4.0-4.3) 4.0 (3.6-4.2) 3.9 (3.7-4.2) 4.0 (3.7-4.2) Clearance (L/day) 0.19 (0.15-0.22) 0.27 (0.20-0.33) 0.28 (0.22-0.35) 0.25 (0.19-0.31) Time to Trough < 10 µg/mL (weeks) 11 (10-12) 7 (6-9) 6 (4-7) 7 (6-9) Forecasted Trough (µg/mL) 26.2 (20.1-34.5) 12.7 (8.6-17.6) 6.3 (3.1-9.4) 11.6 (6.5-19.5) Forecasted Trough < 10 µg/mL 0% (0/17) 31.7% (19/60) 76.5% (26/34) 40.5% (45/111)

Epidemiology of Myocarditis and Pericarditis Following mRNA Vaccination by Vaccine Product, Schedule, and Interdose Interval Among Adolescents and Adults in Ontario, Canada

Increased rates of myocarditis or pericarditis following receipt of COVID-19 mRNA vaccines have been observed. However, few available data are associated with differences in rates of myocarditis or pericarditis specific to vaccine products, which may have important implications for vaccination programs. To estimate rates of reported myocarditis or pericarditis following receipt of a COVID-19 mRNA vaccine by product, age, sex, dose number, and interdose interval. This population-based cohort study was conducted in Ontario, Canada (population: 14.7 million) from December 2020 to September 2021 and used data from Ontario's COVID-19 vaccine registry and passive vaccine-safety surveillance system. All individuals in Ontario, Canada, who received at least 1 dose of COVID-19 mRNA vaccine between December 14, 2020, and September 4, 2021, and had a reported episode of myocarditis or pericarditis following receipt of the COVID-19 vaccine during this period were included. We obtained information on all vaccine doses administered in the province to calculate reported rates of myocarditis or pericarditis. Receipt of a COVID-19 mRNA vaccine (mRNA-1273 [Moderna Spikevax] or BNT162b2 [Pfizer-BioNTech Comirnaty]). All reports of myocarditis or pericarditis meeting levels 1 to 3 of the Brighton Collaboration case definitions were included. Rates and 95% CIs of reported cases of myocarditis or pericarditis per 1 000 000 mRNA vaccine doses administered were calculated by age, sex, dose number, vaccine product, and interdose interval. Among 19 740 741 doses of mRNA vaccines administered, there were 297 reports of myocarditis or pericarditis meeting the inclusion criteria; 228 (76.8%) occurred in male individuals, and the median age of individuals with a reported event was 24 years (range, 12-81 years). Of the reported cases, 207 (69.7%) occurred following the second dose of the COVID-19 mRNA vaccine. When restricted to individuals who received their second dose during the period of enhanced passive surveillance (on or after June 1, 2021), the highest rate of myocarditis or pericarditis was observed in male individuals aged 18 to 24 years following mRNA-1273 as the second dose (299.5 cases per 1 000 000 doses; 95% CI, 171.2-486.4 cases per 1 000 000 doses); the rate following BNT162b2 as the second dose was 59.2 cases per 1 000 000 doses (95% CI, 19.2-138.1 cases per 1 000 000 doses). Overall rates for both vaccine products were significantly higher when the interdose interval was 30 or fewer days (BNT162b2: 52.1 cases per 1 000 000 doses [95% CI, 31.8-80.5 cases per 1 000 000 doses]; mRNA-1273: 83.9 cases per 1 000 000 doses [95% CI, 47.0-138.4 cases per 1 000 000 doses]) compared with 56 or more days (BNT162b2: 9.6 cases per 1 000 000 doses [95% CI, 6.5-13.6 cases per 1 000 000 doses]; mRNA-1273: 16.2 cases per 1 000 000 doses [95% CI, 10.2-24.6 cases per 1 000 000 doses]). The findings of this population-based cohort study of Ontario adolescents and adults with myocarditis or pericarditis following mRNA COVID-19 vaccination suggest that vaccine products and interdose intervals, in addition to age and sex, may be associated with the risk of myocarditis or pericarditis after receipt of these vaccines. Vaccination program strategies, such as age-based product considerations and longer interdose intervals, may reduce the risk of myocarditis or pericarditis following receipt of mRNA vaccines.