Optimal Dosing Interval Research Articles

Population pharmacokinetic model of ABL001/CTX-009 (anti-VEGF/DLL4) in adult cancer patients with solid tumor.

ABL001/CTX-009 is a bispecific antibody targeting delta-like ligand-4 and vascular endothelial growth factor A. In this study, we developed a population pharmacokinetic (PK) model of ABL001/CTX-009 in patients with solid tumors. A total of 712 plasma concentrations from 30 patients with relapsed or refractory solid tumors were collected from a phase 1 study (NCT03292783). A population PK model was developed using a nonlinear mixed-effect method and was evaluated by graphical and numerical methods. Using the model, the steady-state concentrations were simulated to compare weight-based and fixed-dose regimens and to find optimal dosing intervals. The PK of ABL001/CTX-009 was well described by a two-compartment model with a parallel first-order and Michaelis-Menten elimination kinetics. Body weight was selected as a significant covariate on V1. Model evaluation results suggested that the model was adequate and robust with good precision. Simulations after administrations of fixed or weight-based doses showed similar plasma concentrations. Additionally, 10 mg/kg for every other week and 15 mg/kg for every three-week administration showed comparable plasma concentrations. In conclusion, the model well described the plasma concentrations of ABL001/CTX-009 in patients with solid tumors. The simulation suggested that weight-based dose and fixed dose can provide equivalent systemic exposure.

Effect of vaccine dose intervals: Considering immunity levels, vaccine efficacy, and strain variants for disease control strategy

In this study, we present an immuno-epidemic model to understand mitigation options during an epidemic break. The model incorporates comorbidity and multiple-vaccine doses through a system of coupled integro-differential equations to analyze the epidemic rate and intensity from a knowledge of the basic reproduction number and time-distributed rate functions. Our modeling results show that the interval between vaccine doses is a key control parameter that can be tuned to significantly influence disease spread. We show that multiple doses induce a hysteresis effect in immunity levels that offers a better mitigation alternative compared to frequent vaccination which is less cost-effective while being more intrusive. Optimal dosing intervals, emphasizing the cost-effectiveness of each vaccination effort, and determined by various factors such as the level of immunity and efficacy of vaccines against different strains, appear to be crucial in disease management. The model is sufficiently generic that can be extended to accommodate specific disease forms.

Case-cohort design as an efficient approach to evaluating COVID-19 vaccine effectiveness, waning, heterologous immune effect and optimal dosing interval

Though widely applied in other epidemiological fields, the case-cohort study design has seen little application in the field of vaccinology. Case-cohort studies use probabilistic sampling and reweighting to draw inferences about effects (in this case vaccine efficacy) at the population level in an efficient manner. The SARS-CoV-2 pandemic was met with high vaccine uptake, and high rates of population testing prior to the emergence of Omicron variants of concern, in Ontario, Canada, providing an ideal environment for application of case-cohort methodology. We combined a population-based case line list and vaccination database for the province of Ontario between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2 % sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate. First and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68 %, 95 % CI 67 %–69 %; second dose efficacy 88 %, 95 % CI 87–88 %). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95 % CI 0.61–0.67) at 6–8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4–6 months after the second vaccine dose, but rose markedly thereafter. We conclude that a case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination in real time, and also served to quantify the timing and magnitude of infection breakthrough risk in the same cohort. Heterologous vaccination and extended dosing intervals improved the durability of immune response.

Deviation from the recommended schedule: optimal dosing interval foratwo-dose vaccination programme.

Optimizing vaccination impact during an emerging disease becomes crucial when vaccine supply is limited, and robustprotection requires multiple doses. Facing this challenge during the early stages of the COVID-19 vaccine deployment, a pivotal policy question arose: whether to administer a single dose to a larger proportion of the population by deferring the second dose, or to prioritize stronger protection for a smaller subset of the population with the established dosing interval from clinical trials. Usinga delay-differential model and considering waning immunity and distribution capacity, we compared these strategies. We found that the efficacy of the first dose significantly influences the impact ofdelaying the second dose. Even for a relatively low efficacy of the first dose, adelayed strategy may outperform vaccination with the recommended dosing interval in reducing short-term hospitalizations anddeaths despite increase in infections. The optimal delay, however, depends on the specific outcome measured and timelines within which the vaccination strategy is evaluated. We found transition lines for the relative reduction of infection, hospitalization and death below which vaccination with the recommended schedule is the preferred strategy. In a realistic parameter space, our results highlight scenarios in which the conclusions of previous studies are invalid.

Abstract 7162: Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients

Abstract Atezolizumab is an anti-PDL1 approved for treating small cell lung cancer and non-small cell lung cancers. A threshold of 6 µg/ml in plasma has been associated with target engagement with Atezolizumab. The extent to which patients could be overexposed with the standard 1200 mg Q3W flat-dosing remains unknown, but several in silico studies have suggested that flat-dosing with immune checkpoint inhibitors could lead to plasma concentrations far above the necessary levels to be efficacious. Here, we monitored Atezolizumab peak and trough levels in 27 real-world patients with lung cancer as part of routine therapeutic drug monitoring. Individual pharmacokinetic parameters were calculated using a population approach and optimal dosing-intervals were simulated with respect to the target trough levels of Atezolizumab. No patient displayed plasma levels below 6 µg/ml. The results showed that the mean trough level after the first course was 78.3 ± 17 µg/ml, i.e., 13 times above the target concentration associated with target engagement. The overall response rate was 55.5%. Low-grade IRAEs was observed in 37% of patients. No severe immune-related toxicities was observed. On univariate analysis, no relationship was found between exposure metrics of Atezolizumab (i.e., Cmin, Cmax, AUC at the first cycle or during the forthcoming courses) and pharmacodynamic endpoints (i.e., efficacy, toxicity). First-line Atezolizumab treatment and treatment for NSCLC were both significantly associated with efficacy on univariate analysis (p=0.0067 and p=0.0497, respectively), but further multivariate analysis did not confirm this relationship (p=0.2465 and p=0.9981). Smoking status was moderately associated with toxicities on univariate analysis (p=0.03), but this effect was not confirmed on further multivariate analysis (p=0.99). None of the other covariates (i.e., age, sex, NLR, number of metastatic sites, associated chemotherapy) were associated with efficacy or toxicity. Further simulations suggested that the dosing interval could be extended from the standard 21 days (i.e., Q3W) to 49 up to 136 days (mean: 85.7 days, i.e., Q12W dosing), while ensuring plasma levels always above the 6 µg/ml target threshold. This observational, real-world study confirms for the first time in real-world patients that the standard 1200 mg Q3W fixed-dose regimen of Atezolizumab results in significant overexposure in plasma. Of note, this overexposure was not associated with increased side-effects. As plasma levels always exceed pharmacologically active concentrations, the inter-individual variability we observed in PK parameters did not impact efficacy and could not explain differences in response. Our data suggest that dosing intervals could be markedly extended with respect to the target threshold associated with efficacy, thus lowering drug-cost in the future. Citation Format: Sophie Marolleau, Alice Mogenet, Mourad Hamimed, Clara Boeri, Laurent Greillier, Joseph Ciccolini. Killing a fly with a sledgehammer: standard flat-dosing administration of Atezolizumab leads to marked overexposure in real-world lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7162.

Understanding the Interplay of CAR-NK Cells and Triple-Negative Breast Cancer: Insights from Computational Modeling.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have recently emerged as a promising and safe alternative to CAR-T cells for targeting solid tumors. In the case of triple-negative breast cancer (TNBC), traditional cancer treatments and common immunotherapies have shown limited effectiveness. However, CAR-NK cells have been successfully employed to target epidermal growth factor receptor (EGFR) on TNBC cells, thereby enhancing the efficacy of immunotherapy. The effectiveness of CAR-NK-based immunotherapy is influenced by various factors, including the vaccination dose, vaccination pattern, and tumor immunosuppressive factors in the microenvironment. To gain insights into the dynamics and effects of CAR-NK-based immunotherapy, we propose a computational model based on experimental data and immunological theories. This model integrates an individual-based model that describes the interplay between the tumor andthe immune system, along with an ordinary differential equation model that captures the variation of inflammatory cytokines. Computational results obtained from the proposed model shed light on the conditions necessary for initiating an effective anti-tumor response. Furthermore, global sensitivity analysis highlights the issue of low persistence of CAR-NK cells in vivo, which poses a significant challenge for the successful clinical application of these cells. Leveraging the model, we identify the optimal vaccination time, vaccination dose, and time interval between injections for maximizing therapeutic outcomes.

Improving brain penetration using elacridara P-glycoprotein and BCRP inhibitor

The central nervous system (CNS) is a site for a myriad of disorders and diseases, such as schizophrenia, Alzheimers disease, and Parkinsons disease. Many medications targeting these illnesses remain challenged due to efflux transporters forming a blood-brain barrier (BBB). To combat such challenges, elacridar shown promise at inhibiting such transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), therefore improving brain penetration. However, as an early clinical candidate, many remain unknown about elacridars pharmacokinetic (PK) properties in the human body. This paper aims to obtain a better understanding of elacridars pharmacokinetic profile and predict the optimal dose and dose interval for its application in the clinic. To begin with, a series of basic PK models were created using fundamental PK equations and the models were fit to elacridar clinical data to obtain elacridar-specific PK parameters. Next, elacridar preclinical PK as well as in vitro inhibition assay were used to determine the therapeutic window. Our final, multiple-dose extravascular PK model reveals that the most convenient and effective dose regimen is 900 mg BID (bis in die; twice per day). With this elacridar PK model, researchers can leverage elacridar human PK to improve clinical outcomes.

Safety and tolerability study of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity

BackgroundMultiple vaccines have been approved since August 2021 to prevent infection with SARS-CoV-2; however, 20–40% of immunocompromised people fail to develop SARS-CoV-2 spike antibodies after COVID-19 vaccination and remain at high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is a monoclonal neutralizing antibody that binds a conserved epitope on the SARS-CoV-2 spike protein. It is neither renally excreted nor metabolized by P450 enzymes and therefore unlikely to interact with concomitant medications (e.g., immunosuppressive medications). In this open-label feasibility study protocol, we will define the optimal dose and dosing interval of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals as well as its safety and tolerability in this population specifically.MethodsWe will enroll 93 eligible immunocompromised adults with a negative or low-positive (< 50 U/mL) SARS-CoV-2 spike antibody. In phase 1, the first 10 patients will participate in a lead-in pharmacokinetics (PK) cohort study to determine the optimal dosing interval. Phase 2 will expand this population to 50 participants to examine rates of infusion-related reactions (IRR) with a 30-min 500 mg sotrovimab IV infusion. Phase 3 will be an expansion cohort for further assessment of the safety and tolerability of sotrovimab. In phase 4, the first 10 patients receiving 2000 mg IV of sotrovimab on the second sotrovimab infusion day will comprise a lead-in safety cohort that will inform the duration of observation following administration of the drug. The patients will be followed for safety and COVID-19 events for 36 weeks after the second dose.DiscussionIn a previous phase III randomized, placebo-controlled pivotal trial, there were no significant differences in the prevalence of adverse events in patients receiving sotrovimab vs. placebo. Thus, we propose an open-label feasibility study protocol of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals to evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity and define optimal dosing intervals. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures throughout the study.Trial registrationClinicalTrials.gov Identifier: NCT05210101.

Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312)

BackgroundZoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. MethodsWe conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. ResultsBetween November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. ConclusionsAn eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Optimal Administration of Glycyrrhizin Avoids Pharmacokinetic Interactions With High-dose Methotrexate and Exerts a Hepatoprotective Effect.

Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.

Determining the Optimal SARS-CoV-2 mRNA Vaccine Dosing Interval for Maximum Immunogenicity.

Emerging evidence indicates that longer SARS-CoV-2 vaccine dosing intervals results in an enhanced immune response. However, the optimal vaccine dosing interval for achieving maximum immunogenicity is unclear. This study included samples from adult paramedics in Canada who received two doses of either BNT162b2 or mRNA-1273 vaccines and provided blood samples six months (170 to 190 days) after the first vaccine dose. The main exposure variable was vaccine dosing interval (days), categorized as "short" (first quartile), "moderate" (second quartile), "long" (third quartile), and "longest" interval (fourth quartile). The primary outcome was total spike antibody concentrations, measured using the Elecsys SARS-CoV-2 total antibody assay. Secondary outcomes included spike and receptor-binding domain (RBD) immunoglobulin G (IgG) antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to wild-type spike protein and several different Delta variant spike proteins. We fit a multiple log-linear regression model to investigate the association between vaccine dosing intervals and the antibody concentrations. A total of 564 adult paramedics (mean age 40 years, SD=10) were included. Compared to "short interval" (≤30 days), vaccine dosing intervals of the long (39-73 days) group (β= 0.31, 95% Confidence interval (CI): 0.10-0.52) and the longest (≥74 days) group (β = 0.82. 95% CI: 0.36-1.28) were associated with increased spike total antibody concentration. Compared to the short interval, the longest interval quartile was associated with higher spike IgG antibodies, while the long and longest intervals were associated with higher RBD IgG antibody concentrations. Similarly, the longest dosing intervals increased inhibition of ACE-2 binding to viral spike protein. Increased mRNA vaccine dosing intervals longer than 38 days result in higher levels of anti-spike antibodies and ACE-2 inhibition when assessed six months after the first COVID-19 vaccine.

How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis.

Current guidelines for treating cardiac arrest recommend administering 1 mg of epinephrine every 3−5 min. However, this interval is based solely on expert opinion. We aimed to investigate the impact of the epinephrine administration interval (EAI) on resuscitation outcomes in adults with cardiac arrest. We systematically reviewed the PubMed, EMBASE, and Scopus databases. We included studies comparing different EAIs in adult cardiac arrest patients with reported neurological outcomes. Pooled estimates were calculated using the IVhet meta-analysis, and the heterogeneities were assessed using Q and I2 statistics. We evaluated the study risk of bias and overall quality using validated bias assessment tools. Three studies were included. All were classified as “good quality” studies. Only two reported the primary outcome. Compared with a recommended EAI of 3−5 min, a favorable neurological outcome was not significantly different in patients with the other frequencies: for <3 min, odds ratio (OR) 1.93 (95% CI: 0.82−4.54); for >5 min, OR 1.01 (95% CI: 0.55−1.87). For survival to hospital discharge, administering epinephrine for less than 3 min was not associated with a good outcome (OR 1.66, 95% CI: 0.89−3.10). Moreover, EAI of >5 min did not pose a benefit (OR 0.87, 95% CI: 0.68−1.11). Our review showed that EAI during CPR was not associated with better hospital outcomes. Further clinical trials are necessary to determine the optimal dosing interval for epinephrine in adults with cardiac arrest.

Dosing interval strategies for two-dose COVID-19 vaccination in 13 middle-income countries of Europe: Health impact modelling and benefit-risk analysis.

SummaryBackgroundIn settings where the COVID-19 vaccine supply is constrained, extending the intervals between the first and second doses of the COVID-19 vaccine may allow more people receive their first doses earlier. Our aim is to estimate the health impact of COVID-19 vaccination alongside benefit-risk assessment of different dosing intervals in 13 middle-income countries (MICs) of Europe.MethodsWe fitted a dynamic transmission model to country-level daily reported COVID-19 mortality in 13 MICs in Europe (Albania, Armenia, Azerbaijan, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Republic of Moldova, Russian Federation, Serbia, North Macedonia, Turkey, and Ukraine). A vaccine product with characteristics similar to those of the Oxford/AstraZeneca COVID-19 (AZD1222) vaccine was used in the base case scenario and was complemented by sensitivity analyses around efficacies similar to other COVID-19 vaccines. Both fixed dosing intervals at 4, 8, 12, 16, and 20 weeks and dose-specific intervals that prioritise specific doses for certain age groups were tested. Optimal intervals minimise COVID-19 mortality between March 2021 and December 2022. We incorporated the emergence of variants of concern (VOCs) into the model and conducted a benefit-risk assessment to quantify the tradeoff between health benefits versus adverse events following immunisation.FindingsIn all countries modelled, optimal strategies are those that prioritise the first doses among older adults (60+ years) or adults (20+ years), which lead to dosing intervals longer than six months. In comparison, a four-week fixed dosing interval may incur 10.1% [range: 4.3% - 19.0%; n = 13 (countries)] more deaths. The rapid waning of the immunity induced by the first dose (i.e. with means ranging 60-120 days as opposed to 360 days in the base case) resulted in shorter optimal dosing intervals of 8-20 weeks. Benefit-risk ratios were the highest for fixed dosing intervals of 8-12 weeks.InterpretationWe infer that longer dosing intervals of over six months could reduce COVID-19 mortality in MICs of Europe. Certain parameters, such as rapid waning of first-dose induced immunity and increased immune escape through the emergence of VOCs, could significantly shorten the optimal dosing intervals.FundingWorld Health Organization.

Evaluation of the effects of two vancomycin dosing frequencies on the incidence of acute kidney injury in a community hospital: A retrospective pilot study

Objective: Practice guidelines recommend an initial vancomycin dose of 15 to 20 mg/kg of actual body weight (ABW) given intravenously (IV) every 8 to 12 hours in patients with normal renal function.1 Currently at our institution, there is a concern among providers that empiric vancomycin intravenous dosing intervals of eight hours may be associated with an increased rate of nephrotoxicity compared to longer intervals of 12 hours or more. The objective of this study is to evaluate the effects of two vancomycin dosing intervals (eight hours and 12 hours) on renal function. Methods and results: A retrospective chart review was conducted for patients who empirically received vancomycin at a dosing interval of eight hours and 12 hours from 2015 to 2018. Patients at least 18 years old who received vancomycin due to a suspected or proven gram-positive infection and had at least one trough drawn at steady state were included. Patients were excluded if they were pregnant, had renal insufficiency, or if trough levels were not drawn appropriately. The eligible patients were divided into two groups according to the vancomycin dosing intervals (eight hours versus 12 hours), then evaluated for nephrotoxicity. The primary endpoint of this study was the incidence of acute kidney injury (AKI) as defined by Kidney Disease Improving Global Outcomes criteria among the two groups. Seventy patients met the inclusion criteria in the study including 35 patients in the eighthour dosing interval group and 35 patients in the 12-hour dosing interval group. Patients (mean age 52.8) were primarily male (60%), Caucasian (70%), and majority of them received concomitant nephrotoxic agents (60%). Most common vancomycin indication among both groups was skin and soft tissue infection. AKI was observed in two patients (5.7%) in the eight-hour group versus one patient (2.9%) in the 12-hour group, however, the difference was not statistically significant (p=0.552). All three of these patients who developed AKI were also on concurrent nephrotoxic agents, such as intravenous contrast dye and piperacillin/tazobactam. Among the secondary endpoints even though a higher percentage of patients achieved a goal trough level in the eight-hour group compared to patients in the 12-hour group (74% vs. 63% respectively), the results were not statistically significant (p=0.445). Conclusion: No statistically significant difference in rates of AKI was observed among the two dosing interval groups in this study. Patients who experienced AKI were on concomitant nephrotoxic agents and given the small sample size of this feasibility study, the true incidence of AKI due to vancomycin dosing intervals cannot be established. A larger scale study is needed to determine the optimal vancomycin dosing interval.

A Higher Antibody Response Is Generated With a 6- to 7-Week (vs Standard) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Dosing Interval.

The optimal dosing interval for severe acute respiratory syndrome coronavirus 2 vaccines remains controversial. In this prospective study, we compared serology results of paramedics vaccinated with mRNA vaccines at the recommended short (17–28 days) vs long (42–49 days) interval. We found that a long dosing interval resulted in higher spike, receptor binding domain, and spike N terminal domain antibody concentrations.

PHARMACOKINETICS OF SUBCUTANEOUS ALPHA LIPOIC ACID, A PROPOSED THERAPEUTIC AID FOR DOMOIC ACID INTOXICATION IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

Domoic acid (DA) is a potent neurotoxin produced by certain marine algae that can cause neurologic and cardiac dysfunction by activating glutamate receptors. Glutamate receptor overexcitation results in continuous cellular activation, oxidative damage, and cell death. DA toxicosis causes disorientation and seizures, and antiseizure medications are the primary treatment. Alpha lipoic acid (ALA), a powerful antioxidant and glutathione precursor widely used in humans and dogs, can cross the blood-brain barrier to provide antioxidant availability to brain tissue. Hundreds of stranded California sea lions (CSL; Zalophus californianus) are diagnosed annually with DA toxicosis and thus are an appropriate animal in which to establish ALA dosing recommendations for treatment. The objective of this study was to determine the population pharmacokinetics of a single 10- or 20-mg/kg dose of ALA administered subcutaneously into the interscapular region to healthy rehabilitated CSL. Blood was collected at two time points between 15 min and 24 h after administration. Serum ALA concentrations were measured by liquid chromatography-mass spectrometry, and parameters were evaluated using a nonlinear mixed effects model. ALA was rapidly absorbed for each dose, peaking within 20 to 30 minutes, and t1/2 of 40 and 32 min (10 and 20 mg/kg, respectively), followed by an initial steep distribution phase and prolonged elimination phase. Peak concentration (CMAX) was 1,243 ng/ml (10-mg/ml dose) and 5,010 ng/ml (20-mg/ml dose). Serum from 13 CSLd with DA toxicosis treated with 10 mg/kg ALA for 1 to 9 d had measurable levels, and ALA was also measurable in cerebrospinal fluid from two treated CSLs. Therapeutic effects are noted with a CMAX of 4,000 to 5,000 ng/ml in humans; thus in CSLs, 20 mg/kg administered subcutaneously once daily may be sufficient to achieve a therapeutic level in this species. Determination of efficacy and optimal dosing interval and duration require additional investigation.

Feasibility outcomes of a randomised, multicentre, pilot trial comparing standard 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early stage breast cancer

BackgroundAdjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. MethodsEligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. ResultsAll 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36–88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. ConclusionsAll study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial.Trial registration: NCT03664687.

S0807 Ustekinumab Dose Intensification in Patients With Crohn’s Disease: Comparing Every 4 and Every 6-Week Dosing

INTRODUCTION: Ustekinumab (UST) therapy for Crohn’s disease (CD) consists of an induction infusion followed by maintenance injections every 8 weeks (q8). However, some pts lose response to this standard dosing. Dose intensification from q8 to q4 has been shown to be safe and effective. However, there is no data comparing outcomes of q4 dosing to q6 dosing. We sought to compare characteristics and clinical outcomes among pts with CD by intensified UST dose interval. METHODS: Retrospective cohort study of adult pts with CD undergoing UST dose intensification at a tertiary referral center between 1/1/2016 and 1/31/2019. Electronic medical records were reviewed for demographics, laboratory data, and CD history. Outcomes assessed within 12 months after dose intensification included corticosteroid-free remission (i.e. Harvey-Bradshaw Index [HBI] < 5 with no use of systemic corticosteroids), change to new biologic therapy, clinical response (i.e. reduction in HBI >3 points for pts with HBI >5), endoscopic improvement, improvement in CT or MRI abdomen, initiation of systemic corticosteroids, IBD surgery, IBD hospitalization, normalization of elevated C-reactive protein (CRP), and normalization of elevated fecal calprotectin. Student’s t-test and Pearson’s chi-squared test were used to compare characteristics and outcomes between q4 and q6 groups. Logistic regression was performed to determine the association between UST dose interval and corticosteroid-free remission. RESULTS: We identified 238 pts who initiated UST for CD. Among these pts, 123 (51.7%) underwent dose intensification to q4 (n = 64), q5 (n = 1), q6 (n = 55), or q7 (n = 3). Characteristics and outcomes by q4 and q6 dosing are presented in Tables 1 and 2, respectively. There were no significant differences in outcomes including remission, change to new biologic, clinical response, imaging or endoscopic improvement, surgery, hospitalization, initiation of corticosteroids, and normalization of CRP or fecal calprotectin. Logistic regression demonstrated no association between UST dose interval and corticosteroid-free remission (q6 vs. q4 OR 1.0, 95% CI 0.4–2.2). CONCLUSION: Dose intensification of UST can be effective to regain response, however there is little guidance on dosing intervals. In this study, q4 dosing was not found to be more effective than q6 dosing. Larger, prospective studies are needed to determine the optimal and most cost-effective dose interval among pts who lose response to standard UST dosing.Table 1Table 2

The appropriate dose of propofol for anesthesia induction in morbidly obese patients.

To investigate the optimal dose of propofol in patients with morbid obesity when the anesthetic induction dosage is calculated based on lean body weight (LBW). Forty morbid obese patients with body mass index (BMI) ≥35 kg/m2 were randomly divided into two groups: B and M. The sequential method was used in group B to study the EC50 and 95% confidence interval (CI) that met a bispectral index (BIS) value of <50 (the initial dose was set at 2.5 mg/kg). The sequential method was used in group M to obtain the EC50 and 95% CI (the initial dose was set as 3.0 mg/kg) satisfying the mean arterial pressure (MAP) fluctuation margin of >40%. The optimal dose interval of propofol was obtained by synthetically analyzing the results of the two-sequence method. There was no significant difference in the general condition between the two groups (P>0.05). There was no significant change in vital signs from when patients entered the operating room to when sufentanil was infused (P>0.05). The probit model of group B was Y=-5.411+2.343X, the EC50 of positive reaction with BIS <50 was 2.310 mg/kg, and 95% CI was 1.850-2.883 mg/kg. The probit model in the M group was Y=3.275 - 0.918X, the EC50 of positive reaction that reached >40% of the whole process of anesthetic induction was 3.567 mg/kg, and 95% CI was 1.233-7.165 mg/kg. The appropriate dosage of propofol was 2.310-3.567 mg/kg when the anesthetic induction dosage for patients with morbid obesity was calculated based on LBW. With this dose, the depth of intubation is satisfactory and the hemodynamics are stable.

Simultaneous Quantitation of S(+)- and R(-)-Baclofen and Its Metabolite in Human Plasma and Cerebrospinal Fluid using LC-APCI-MS/MS: An Application for Clinical Studies.

Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood–brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5μ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.