Empirical Dose Research Articles

ODP463 Assess the Usefulness of Pre–Ablation Diagnostic I-123 Iodine Scans in Patients with Differentiated Thyroid Cancer

Abstract Context: Over the last decade, there have been significant changes in the post-operative management of Differentiated Thyroid cancer. The use of Diagnostic 123-Iodine scans has become controversial as many endocrinology practices now give empiric doses of RAI (Radioactive Iodine) when needed based on risk stratification. Allegheny Health Network (AHN) routinely uses I-123 Pre RAI scans prior to ablative or adjuvant therapy. As per the 2015 ATA (American Thyroid Association) guidelines – Pre therapy scans and/or measurement of thyroid bed uptake may be useful when the extent of the thyroid remnant cannot be accurately ascertained from the surgical report or neck ultrasonography, or when the results would alter either the decision to treat or alter the activity of RAI dose that is administered. ATA recommendation is vague and further studies are needed to identify these patients who need pretreatment scan. Objective The objective of our study is to evaluate the utility of pre-therapy diagnostic 131-I scan for the risk stratification and Radioactive Iodine administration decisions in patients with Differential Thyroid cancer after thyroidectomy. Design: The study is a retrospective blinded chart review of cases at AHN. Setting: The study was conducted at an academic tertiary care center of a large Health Network in Western Pennsylvania. Method: Retrospective chart review of patients at AHN who underwent RAI treatment from 2016-2021 has been completed. 195 patients with Differentiated Thyroid cancer have been included in this study. These patients had a pre-therapy WBI (Whole Body Iodine) scan as per AHN's current clinical practice. Data collection includes demographic information, surgical details including lymph neck dissection performed or not, tumor histopathology, TNM classification, post thyroidectomy labs including TSH (Thyroid Stimulating Hormone), TG (Thyroglobulin) and TGA (Thyroglobulin antibody), pre and post-operative ultrasound, RAI dose, Pre-therapy scan findings and Post therapy RAI scan findings. Intervention: Using clinical and histopathology information a group of blinded endocrinologist are performing risk stratification to determine postoperative management with respect to radioiodine therapy (RAI) planning. The decision to withhold or to administer RAI, and the recommended low, medium or high 123-I activity will be decided by them without having information from the Diagnostic 123-Iodine scans. Main Outcome Measure: Main outcome measures will be difference in risk stratification and management with and without Diagnostic 123-Iodine scans. We plan to compare this empiric management strategy to the actual management strategy that took place based on the Pre-therapy scan. Results This will include percentage of patients where decision to treat or dose of radioactive iodine was different, when information from Diagnostic 123-Iodine scan was not available. This will help streamline Endocrinologist practice for patients with Differentiated Thyroid cancer. Presentation: No date and time listed

A Real-World Matched Cohort Study of the Effect of Concomitant Amiodarone or Diltiazem Administration on Apixaban Peak and Trough Concentrations.

Apixaban is a substrate for p-glycoprotein and is extensively metabolized by cytochrome P450 (CYP)3A4. There are minimal published data regarding the effect of amiodarone and diltiazem on apixaban serum concentrations. The aim of this study was to determine the degree of elevation of apixaban concentrations resulting from amiodarone or diltiazem. This was a matched cohort study approved by the Institutional Review Board. Patients receiving apixaban 5 mg twice daily with concomitant diltiazem or amiodarone were enrolled. Control groups were enrolled via matching characteristics of sex, age, weight, creatinine clearance, and statin therapy. Exclusions were an inappropriate dosage of apixaban or concomitant dronedarone, verapamil, ranolazine, naproxen, or both amiodarone and diltiazem. Blood samples were collected 3-4h after and 0.5-2h before an apixaban dose, corresponding to peak and trough concentrations, respectively. Results were compared using a t test. Thirty patients were enrolled in each of the four groups. The mean peak apixaban concentration was 239±82 ng/mL in the amiodarone group and 208±66 ng/mL in the corresponding control group (p=0.068). Trough concentrations were 142±71 ng/mL and 117±41 ng/mL, respectively (p=0.055). The mean peak apixaban concentration was 243±99 ng/mL in the diltiazem group and 213±82 ng/mL in the control group (p=0.11). Trough concentrations were 130±65 ng/mL and 108±54 ng/mL, respectively (p=0.09). Coadministration of amiodarone and diltiazem resulted in a trend toward increased apixaban concentrations. The extent of elevation suggests that empiric dose changes are not necessary; however, individual patients may benefit from monitoring and dose adjustment.

The use of drug monitoring of infliximab and adalimumab to optimize the treatment of inflammatory bowel diseases in children

Introduction. The effectiveness of the use of TNF inhibitors in patients with inflammatory bowel diseases (IBD) has been shown. 20-40% of patients are known to fail to respond to received therapy, and 10-30% of patients experience a loss of effect by the year of therapy. Objective is to evaluate the information content of therapeutic drug monitoring (TDM) for effective treatment with TNF blockers (infliximab - IFX, adalimumab - ADA) in IBD children. Materials and methods. There were examined seventy four children on IFX therapy including 66 children on ADA therapy. The age of the children ranged from 3.4 to 18 years. Residual levels of IHF and ADA were determined using a lateral flow immunoassay. Statistical data processing was performed using the Statistica 10.0, SPSS 16 software. Differences between groups were assessed using the nonparametric Mann-Whitney U test. Results. IFX levels (less than 3 µg/ml) were detected in 64% of cases, ADA (less than 5 µg/ml) in 21% of cases. The residual level of IFX and ADA in remission significantly exceeded the level of drugs in groups of children in exacerbation. An inverse relationship was observed between the residual level of IFX (r = -0.68, p = 0.000) and ADA (r = -0.31, p = 0.000) and the number of days after drug administration. Anti-IFX antibodies were found in 27.3% in the exacerbation group and in 5.8% in remission (p < 0.001). Antibodies to ADA in children with IBD were found in 4 patients with a low concentration of the drug (2.57 ± 0.45 µg/ml) in the serum in a state of exacerbation. In patients on anti-TNF therapy, empirical dose selection revealed a residual level lower than in children in whom dose adjustment was carried out taking into account the residual concentration of drugs. Conclusion. The use of TDM TNF blockers in combination with the determination of antibodies to drugs can significantly increase the effectiveness of therapy in IBD children.

Sugammadex to Facilitate Neurologic Assessment in Severely Brain-Injured Patients: A Retrospective Analysis and Practical Guidance.

Background Widely used in anesthetic management, sugammadex is increasingly employed in the reversal of neuromuscular blocking agents (NMBAs) in the emergency department and critical care arena, where little evaluative data currently exists. This study explored the utility and safety of using sugammadex to facilitate neurologic assessmentsin critically ill, NMBA-exposed patients. Methods We pursued a retrospective case series and single-arm cohort analysis of all brain-injured patientsreceiving sugammadex to facilitate neurologic evaluation during one year at a high-volume Level 1 trauma center. The primary outcome was the qualitative impact of sugammadex administration on neurosurgeon decision-making. Secondary outcomes included the change to Glasgow Coma Scale (GCS) and hemodynamic parameters compared before and after sugammadex administration.Sugammadex dosing was also assessed across various weight scalars to explore dose-response trends and generate preliminary guidance for use in this setting. Results Our study criteria yielded 12 sugammadex administrations across 11 patients, the majorityof whom had sustained a traumatic brain injury.All sugammadex administrations were adjudicated as beneficial to neurosurgeon decision-making and 50% were associated with a change to prognosis and plan. Sugammadex was associated with an increase in the GCSof 1-8 points among the 67% of patients who responded. Mean arterial pressure decreased significantly after sugammadex administration (median 94 vs. 104 mmHg, p=0.0215, median change of -8 mmHg [95%CI -25-3 mmHg]). No apparent dose-response trends were observed for changes to GCS or hemodynamic parameters. Conclusions The use of sugammadex to facilitate neurologic assessment after NMBA exposure in brain-injured patients was frequently associated with clinically meaningful changes to the neurologic exam and treatment plan. The risks of hemodynamic compromise and care complexity should be collaboratively weighed before pursuing this modality.An empiric sugammadex dose of 200 mg appears reasonable for this purpose, but further evaluation of NMBA reversal in the neurocritically ill outside of procedural settings is warranted.

Rational determination of cefazolin dosage regimen in horses based on pharmacokinetics/pharmacodynamics principles and Monte Carlo simulations.

A pharmacokinetics/pharmacodynamics (PK/PD) approach was used to determine the best empirical dosage regimen of cefazolin (CEZ) after intramuscular (IM) administration of CEZ in horses. Seven horses received a single IM or intravenous (IV) administration of CEZ of 5mg/kg bodyweight (BW) according to a crossover design. CEZ plasma concentrations were measured using LC-MS/MS. The plasma concentrations in these seven horses and those of six other horses obtained in a previous study with an IV CEZ dose of 10mg/kg were modelled simultaneously using NonLinear Mixed-Effect modelling followed by Monte Carlo simulations to establish a rational dosage regimen. A 90% Probability of Target Attainment (PTA) for a PK/PD target of a free plasma concentration exceeding MIC90 (fT > MIC ) for 40% of the dosing interval was set for selecting an effective dosing regimen. The typical half-life of absorption and bioavailability after IM administration were 1.25 h and 96.8%, respectively. A CEZ dosage regimen of 5mg/kg BW q12h IM administration achieved therapeutic concentrations to control both Streptococcus zooepidemicus and Staphylococcus aureus. For the same dose, the fT > MIC after IM administration was significantly longer than after IV administration, and the IM route should be favoured by clinicians for its efficiency and convenience.

Evaluating the Effects of Ertapenem and Meropenem on Tacrolimus

Purpose: Further elucidate the potential drug interaction between tacrolimus and carbapenems in order to appropriately maintain the balance between infection treatment and therapeutic immunosuppression. Methods: This study was a retrospective evaluation of solid organ transplant recipients on a stable dose of tacrolimus who received either ertapenem or meropenem. Patients were excluded if they had acute kidney injury, acute liver failure, concomitant initiation of medications that interact with tacrolimus, or were pregnant. The primary endpoint was the change in the median daily tacrolimus dose after meropenem or ertapenem administration. The secondary endpoint was the change in serum tacrolimus levels after meropenem or ertapenem administration. Results: A total of 28 patients on tacrolimus were included in the study, 12 received ertapenem and 16 received meropenem. The median daily tacrolimus dose was 4.5 mg [IQR 3.0 mg – 8.8 mg] prior to and 3.4 mg [IQR 2.3 mg – 8.8 mg] after ertapenem administration. The median daily tacrolimus dose was 3.0 mg [IQR 1.6 mg – 5.5 mg] before and 3.0 mg [IQR 1.6 mg – 5.5 mg] after meropenem administration. No statistically significant difference in regard to the change in the median daily tacrolimus dose after ertapenem (P =.173) or meropenem administration (P =.755) was observed. There was no statistically significant difference found after ertapenem (P =.583) or meropenem (P =.317) administration when comparing pre- and post-administration median serum tacrolimus levels. Conclusion: The administration of ertapenem or meropenem did not affect serum tacrolimus levels or daily tacrolimus dose suggesting against empiric dose adjustments with co-administration.

Examining D-dimer and Empiric Anti-coagulation in COVID-19-Related Thrombosis.

ObjectiveThrombosis is thought to occur frequently in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to elucidate the relationship between macro/microvascular thrombosis, D-dimer levels, and empiric anticoagulation in coronavirus disease 2019 (COVID-19).MethodsThis was an exploratory prospective, single-site, observational study. Adult emergency department patients with COVID-19 requiring hospitalization received a point-of-care lower extremity venous duplex ultrasound. The primary endpoint was thromboembolism and associated D-dimer level. Secondary endpoints included rates of micro and macro thrombotic complications as well as empiric anticoagulant use.ResultsBetween January 13th and April 12th 2021, 52 patients were enrolled. Median D-dimer at presentation was 650 ng/mL (range 250-10,000 ng/mL) among patients with negative duplex studies. During hospitalization, 18 patients underwent 20 additional studies assessing for venous thromboembolism (VTE). These studies yielded one deep vein thrombosis (DVT) diagnosis. Among patients with negative studies median D-dimer was 1,246 ng/mL (range 329-10,000 ng/mL). Two patients experienced microvascular complications. Seven patients were started on empiric full dose anticoagulation.ConclusionWhile VTE remains a major concern amongst patients with COVID-19, the normal D-dimer cut off of >500 ng/mL likely should not be used to initiate further VTE workup. Additionally, moderately elevated D-dimer did not correlate strongly with microvascular complications and may not be relevant in the decision to initiate empiric anticoagulation.

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS.

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D3-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min−1. The method’s selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8–105.2%), matrix effect (92.3–106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5–500 ng·mL−1, 2–500 ng·mL−1, and 0.5–200 ng·mL−1 for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.

O-129 Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss: a scientific impact paper

Abstract Study question How should subclinical hypothyroidism (SCH) and autoimmune thyroid disease (ATD) be managed in women with subfertility or recurrent pregnancy loss? Summary answer This Royal College of Obstetricians and Gynaecologists (RCOG) scientific impact paper provides evidence based recommendations on the testing for and management of SCH and ATD. What is known already Subclinical hypothyroidism and autoimmune thyroid disease have been linked to adverse pregnancy outcomes such as miscarriage and premature birth. There is debate about whether there should be routine testing of thyroid function in both the general population and individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or recurrent pregnancy loss (RPL). Study design, size, duration The purpose of this scientific impact paper is to provide evidence based clinical practice recommendations about the controversial subjects of SCH and antithyroid autoantibodies in women with a history of subfertility or RPL. This has been done by reviewing and collating the published evidence and international guidance. Participants/materials, setting, methods This body of work is a literature review of published primary studies, systematic reviews and international guidelines relating to the screening for and management of SCH and ATD in women with subfertility or recurrent pregnancy loss. Recommendations for practice and areas for further research have been identified. Main results and the role of chance Population-trimester and laboratory-specific reference ranges for serum thyroid stimulating hormone (TSH) and free thyroxine (fT4) should be applied when defining SCH. Untreated mild–moderate SCH (TSH 4.0-10.0mIU/l) is associated with early pregnancy loss and there is low-quality evidence that levothyroxine (LT4) treatment of such women is associated with improved pregnancy and live birth rates. Routine preconception TSH and fT4 testing should be offered to women with history of RPL or subfertile women undergoing assisted reproduction. Women receiving LT4 treatment for SCH should have an empirical dose increase in pregnancy, doubling the dose on 2days per week once pregnancy is confirmed, with regular TSH measurements from 7–9weeks gestation. There is no benefit from LT4 treatment in improving pregnancy outcomes for euthyroid TPOAb-negative women. Knowing TPOAb status allows for stratification of women who will require thyroid function monitoring during pregnancy. The option of performing preconception TPOAb testing for women with infertility or a history of RPL versus routine early pregnancy thyroid function testing alone are both acceptable strategies, until clinical and cost-effectiveness analyses are available. Further studies are required to determine the role of selenium or steroids in improving pregnancy outcomes for euthyroid TPOAb-positive women. Limitations, reasons for caution The evidence for treatment of SCH in women with RPL or subfertility is of low quality and therefore must be interpreted with caution. Wider implications of the findings SCH and ATD are common conditions and management strategies are widely debated, particularly in women with history of subfertility or recurrent pregnancy loss. Further high quality studies are needed in this area to help strengthen our knowledge on how to manage such patients. Trial registration number Not applicable

Modeling the impact of spatial oxygen heterogeneity on radiolytic oxygen depletion during FLASH radiotherapy

Purpose. It has been postulated that the delivery of radiotherapy at ultra-high dose rates (‘FLASH’) reduces normal tissue toxicities by depleting them of oxygen. The fraction of normal tissue and cancer cells surviving radiotherapy depends on dose and oxygen levels in an exponential manner and even a very small fraction of tissue at low oxygen levels can determine radiotherapy response. To quantify the differential impact of FLASH radiotherapy on normal and tumour tissues, the spatial heterogeneity of oxygenation in tissue should thus be accounted for. Methods. The effect of FLASH on radiation-induced normal and tumour tissue cell killing was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen depletion (ROD) over domains with simulated capillary architectures. To study the impact of heterogeneity, two architectural models were used: (1) randomly distributed capillaries and (2) capillaries forming a regular square lattice array. The resulting oxygen partial pressure distribution histograms were used to simulate normal and tumour tissue cell survival using the linear quadratic model of cell survival, modified to incorporate oxygen-enhancement ratio effects. The ratio (‘dose modifying factors’) of conventional low-dose-rate dose and FLASH dose at iso-cell survival was computed and compared with empirical iso-toxicity dose ratios. Results. Tumour cell survival was found to be increased by FLASH as compared to conventional radiotherapy, with a 0–1 order of magnitude increase for expected levels of tumour hypoxia, depending on the relative magnitudes of ROD and tissue oxygen metabolism. Interestingly, for the random capillary model, the impact of FLASH on well-oxygenated (normal) tissues was found to be much greater, with an estimated increase in cell survival by up to 10 orders of magnitude, even though reductions in mean tissue partial pressure were modest, less than ∼7 mmHg for the parameter values studied. The dose modifying factor for normal tissues was found to lie in the range 1.2–1.7 for a representative value of normal tissue oxygen metabolic rate, consistent with preclinical iso-toxicity results. Conclusions. The presence of very small nearly hypoxic regions in otherwise well-perfused normal tissues with high mean oxygen levels resulted in a greater proportional sparing of normal tissue than tumour cells during FLASH irradiation, possibly explaining empirical normal tissue sparing and iso-tumour control results.

Weight-adjusted dosing of fibrinogen concentrate and cryoprecipitate in the treatment of hypofibrinogenaemic bleeding adult cardiac surgical patients: a post hoc analysis of the Fibrinogen Replenishment in cardiac surgery randomised controlled trial.

Hypofibrinogenaemia is associated with excessive bleeding after cardiac surgery. Our aim was to compare the efficacy and safety of weight-adjusted vs empiric dosing of fibrinogen replacement in cardiac surgery. In the Fibrinogen Replenishment in Cardiac Surgery (FIBRES) RCT, patients (n=735) received fibrinogen concentrate (4 g) or cryoprecipitate (10 units). In this post-hoc analysis, patients were grouped into quartiles based on increasing weight-adjusted dosing. Generalised estimating equations were used to account for hospital site, age, sex, surgical complexity, urgency, and critical preoperative status. The primary outcome was the number of units of red blood cells transfused within 24 h of cardiopulmonary bypass. Secondary outcomes included allogeneic blood components within 24 h, tamponade or major bleeding, and thromboembolic complications, ischaemic complications, or both within 28 days of cardiopulmonary bypass. The median weight-adjusted doses were 52 mg kg-1 of fibrinogen concentrate (inter-quartile range [IQR], 45-61; n=372) and 1.30 units per 10 kg of cryoprecipitate (IQR, 1.11-1.54; n=363). When patients were divided into quartiles of lowest to highest weight-adjusted dosing, no differences were seen in the primary outcome of red blood cell units transfused within 24 h of cardiopulmonary bypass between the lowest and highest quartiles in either the fibrinogen group (adjusted relative risk [RR]=0.90; 95% confidence interval [CI], 0.71-1.13; P=0.36) or the cryoprecipitate group (adjusted RR=1.04; 95% CI, 0.76-1.43; P=0.80). Results were similar for all secondary outcomes. Outcomes for the lowest and highest weight-adjusted doses of fibrinogen replacement were comparable. Weight-adjusted dosing does not appear to offer advantages over empiric dosing in this context. NCT03037424.

Comparison of Race-Based and Non-Race-Based Equations for Kidney Function Estimation in Critically Ill Thai Patients for Vancomycin Dosing.

Empiric antibiotic dosing frequently relies on an estimate of kidney function based on age, serum creatinine, sex, and race (on occasion). New non–race‐based estimated glomerular filtration rate (eGFR) equations have been published, but their role in supporting dosing is not known. Here, we report on a population pharmacokinetic model of vancomycin that serves as a useful probe substrate of eGFR in critically ill Thai patients. Data were obtained from medical records during a 10‐year period. A nonlinear mixed‐effects modeling approach was conducted to estimate vancomycin parameters. Data from 208 critically ill patients (58.2% men and 36.0% septic shock) with 398 vancomycin concentrations were collected. Twenty‐three covariates including 12 kidney function estimates were tested and ranked on the basis of the model performance. The median (min, max) age, weight, and serum creatinine was 69 (18, 97) years, 60.0 (27, 120) kg, and 1.53 (0.18, 7.15) mg/dL, respectively. The best base model was a 1‐compartment linear elimination with zero‐order input and proportional error model. A Thai‐specific eGFR equation not indexed to body surface area model best predicted vancomycin clearance (CL). The typical value for volume of distribution and CL was 67.5 L and 1.22 L/h, respectively. A loading dose of 2000 mg followed by maintenance dose regimens based on eGFR is suggested. The Thai GFR not indexed to BSA model best predicts vancomycin CL and dosing in the critically ill Thai population. A 5% to 10% absolute gain in the vancomycin probability of target attainment is expected with the use of this population‐specific eGFR equation.

Does calculation method matter for targeting vancomycin area under the curve?

To assess differences in vancomycin AUC estimates from two common, clinically applied first-order pharmacokinetic equation methods compared with Bayesian estimates. A cohort of patients who received vancomycin and therapeutic drug monitoring was studied. First-order population pharmacokinetic equations were used to guide initial empirical dosing. After receipt of the first dose, patients had peak and trough serum levels drawn and steady-state AUC was estimated using first-order pharmacokinetic equations as standard care. We subsequently created a Bayesian model and used individual Empirical Bayes Estimates to precisely calculate vancomycin AUC24-48, AUC48-72 and AUC72-96 in this cohort. AUC at steady state (AUCSS) differences from the first-order methods were compared numerically and categorically (i.e. below, within or above 400-600 mg·h/L) to Bayesian AUCs, which served as the gold standard. A total of 65 adult inpatients with 409 plasma samples were included in this analysis. A two-compartment intravenous infusion model with first-order elimination fit the data well. The mean of Bayesian AUC24-48 was not significantly different from AUC estimates from the two first-order pharmacokinetic equation methods (P = 0.68); however, Bayesian AUC48-72 and Bayesian AUC72-96 were both significantly different when compared with both first-order pharmacokinetic equation methods (P < 0.01 for each). At the patient level, categorical classifications of AUC estimates from the two first-order pharmacokinetic equation methods differed from categorizations derived from the Bayesian calculations. Categorical agreement was ∼50% between first-order and Bayesian calculations, with declining categorical agreement observed with longer treatment courses. Differences in categorical agreement between calculation methods could potentially result in different dose recommendations for the patient. Bayesian-calculated AUCs between 48-72 and 72-96 h intervals were significantly different from first-order pharmacokinetic method-estimated AUCs at steady state. The various calculation methods resulted in different categorical classification, which could potentially lead to erroneous dosing adjustments in approximately half of the patients.

Venous thromboembolism in COVID-19 patients and prediction model: a multicenter cohort study

BackgroundPatients with COVID-19 infection are commonly reported to have an increased risk of venous thrombosis. The choice of anti-thrombotic agents and doses are currently being studied in randomized controlled trials and retrospective studies. There exists a need for individualized risk stratification of venous thromboembolism (VTE) to assist clinicians in decision-making on anticoagulation. We sought to identify the risk factors of VTE in COVID-19 patients, which could help physicians in the prevention, early identification, and management of VTE in hospitalized COVID-19 patients and improve clinical outcomes in these patients.MethodThis is a multicenter, retrospective database of four main health systems in Southeast Michigan, United States. We compiled comprehensive data for adult COVID-19 patients who were admitted between 1st March 2020 and 31st December 2020. Four models, including the random forest, multiple logistic regression, multilinear regression, and decision trees, were built on the primary outcome of in-hospital acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and tested for performance. The study also reported hospital length of stay (LOS) and intensive care unit (ICU) LOS in the VTE and the non-VTE patients. Four models were assessed using the area under the receiver operating characteristic curve and confusion matrix.ResultsThe cohort included 3531 admissions, 3526 had discharge diagnoses, and 6.68% of patients developed acute VTE (N = 236). VTE group had a longer hospital and ICU LOS than the non-VTE group (hospital LOS 12.2 days vs. 8.8 days, p < 0.001; ICU LOS 3.8 days vs. 1.9 days, p < 0.001). 9.8% of patients in the VTE group required more advanced oxygen support, compared to 2.7% of patients in the non-VTE group (p < 0.001). Among all four models, the random forest model had the best performance. The model suggested that blood pressure, electrolytes, renal function, hepatic enzymes, and inflammatory markers were predictors for in-hospital VTE in COVID-19 patients.ConclusionsPatients with COVID-19 have a high risk for VTE, and patients who developed VTE had a prolonged hospital and ICU stay. This random forest prediction model for VTE in COVID-19 patients identifies predictors which could aid physicians in making a clinical judgment on empirical dosages of anticoagulation.

Key Factors in Effective Patient-Tailored Dosing of Fluoroquinolones in Urological Infections: Interindividual Pharmacokinetic and Pharmacodynamic Variability.

Fluoroquinolones (FQs) are a critical group of antimicrobials prescribed in urological infections as they have a broad antimicrobial spectrum of activity and a favorable tissue penetration at the site of infection. However, their clinical practice is not problem-free of treatment failure, risk of emergence of resistance, and rare but important adverse effects. Due to their critical role in clinical improvement, understanding the dose-response relation is necessary to optimize the effectiveness of FQs therapy, as it is essential to select the right antibiotic at the right dose for the right duration in urological infections. The aim of this study was to review the published literature about inter-individual variability in pharmacological processes that can be responsible for the clinical response after empiric dose for the most commonly prescribed urological FQs: ciprofloxacin, levofloxacin, and moxifloxacin. Interindividual pharmacokinetic (PK) variability, particularly in elimination, may contribute to treatment failure. Clearance related to creatinine clearance should be specifically considered for ciprofloxacin and levofloxacin. Likewise, today, undesired interregional variability in FQs antimicrobial activity against certain microorganisms exists. FQs pharmacology, patient-specific characteristics, and the identity of the local infecting organism are key factors in determining clinical outcomes in FQs use.

Predictors of Hypothyroidism Following Empirical Dose Radioiodine in Toxic Thyroid Nodules: Real-Life Experience

ObjectiveWe aimed to determine the factors predicting hypothyroidism after radioactive iodine (RAI) treatment in patients with toxic adenoma and toxic multinodular goiter. MethodsWe retrospectively collected the data of 237 patients with toxic multinodular goiter or toxic adenoma who had consecutively received RAI treatment between 2014 and 2020 at 2 medical centers. Patients who received the second RAI treatment and whose medical records could not be accessed were excluded from the study. Finally, 133 patients were included in the study. RAI was administered at an empirical dose of 15 or 20 mCi. ResultsThe median age of the 133 participants was 69 years (interquartile range, 62-75 years), and 64.7% of the participants were women. A total of 42.1% of the patients had toxic adenoma, whereas 57.9% of patients had toxic multinodular goiter. The median follow-up was 24 months (interquartile range, 11-38 months). During the follow-up, 61.7% of patients became euthyroid, 30.8% developed hypothyroidism, and 7.5% remained hyperthyroid. The median month of hypothyroidism onset was 4 months (interquartile range, 2-9 months). Regression analysis revealed 2 factors that could predict hypothyroidism: thyroid-stimulating hormone (odds ratio, 2.548; 95% CI, 1.042-6.231; P = .04) and thyroid volume (odds ratio, 0.930; 95% CI, 0.885-0.978; P = .005). ConclusionOverall, 30.8% of the cases developed hypothyroidism after the RAI treatment. Approximately 78% of hypothyroidism developed within the first 10 months. The risk of hypothyroidism was higher in patients with higher thyroid-stimulating hormone and smaller thyroid volume.

Deprescribing in type 2 diabetes and cardiovascular disease: Recommendations for safe and effective initiation of glucagon-like peptide-1 receptor agonists in patients on insulin therapy

Select glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular benefits in both primary and secondary prevention populations and are recommended in multiple guidelines for cardiovascular risk reduction in people with type 2 diabetes (T2D). Despite this, uptake of GLP-1 receptor agonists in clinical practice has been lagging. While the etiology of their underuse is multifactorial, lack of comfortability in adding a GLP-1 receptor agonist to established insulin regimens is a common barrier. Adjustments to basal and bolus insulin doses upon initiation of GLP-1 receptor agonists in trials have varied. When recommending empiric dose adjustments during initiation of GLP-1 receptors agonists, the most recent A1C and the current blood glucose levels, if available, should be taken into consideration. When initiating in a person being managed with basal-only insulin regimens, an empiric 20 % dose reduction is recommended if the baseline A1C is ≤8 %. For individuals using intensive insulin regimens, empiric dose reductions of up to 25 % in basal and 50 % in bolus therapy were implemented and summarized further in this review. Overall, initiation of GLP-1 receptor agonists can decrease insulin requirements and may permit deintensification of antihyperglycemic therapy through the reduction or discontinuation of bolus insulin therapy. As a result, this simplified regimen promotes increased adherence, reduces glycemic variability and hypoglycemia, and improves overall glycemic management and quality of life. This review aims to serve as a guide for clinicians to facilitate the initiation of GLP-1 receptor agonists and deintensification of insulin by providing suggested dose adjustments based on available literature.

Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25–21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan–Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30–60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.

Evaluation of the Pharmacokinetic Interaction Between Letermovir and Tacrolimus in Allogeneic Hematopoietic Cell Transplantation Recipients

Data describing the magnitude of the pharmacokinetic interaction between letermovir and tacrolimus in allogeneic hematopoietic cell transplantation (allo-HCT) recipients are limited, and varying outcomes have been reported. The need for empiric dose adjustment of tacrolimus on initiation of letermovir has not been established; instead, guidelines suggest closely monitoring the tacrolimus trough concentration and adjusting the dose as needed. A better understanding of this interaction is imperative to accurately manage the narrow therapeutic window of tacrolimus post-transplantation. The primary objective of this study was to determine the percent change in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir. Secondary objectives were to describe the frequency of tacrolimus dose adjustments after initiation of letermovir, the percent change in daily tacrolimus dose over the 14-day period after initiation of letermovir, and the incidence of both subtherapeutic and supratherapeutic tacrolimus trough concentrations. This retrospective chart review included adult allo-HCT recipients at our institution who received tacrolimus in combination with oral letermovir and had been taking tacrolimus for at least 5 days before letermovir initiation. Patients receiving strong CYP3A4 inhibitors or i.v. tacrolimus were excluded. Thirty-five patients were included in the analysis. The median percent increase in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir was 22% on days 2 to 4, 47% on days 5 to 7, 66% on days 8 to 11, and 81% on days 12 to 14. The mean frequency of tacrolimus dose adjustments was 0.66 on days 2 to 4, 0.69 on days 5 to 7, 1.06 on days 8 to 11, and 0.57 on days 12 to 14. The results of this study show that the pharmacokinetic interaction between tacrolimus and letermovir is substantial and continues to affect tacrolimus concentration over the 14-day period after letermovir initiation. Close monitoring of tacrolimus trough concentration on initiation of letermovir should be considered.

Pharmacokinetic Impact of Posaconazole Discontinuation on Tacrolimus Levels in Heart Transplant Recipients

<h3>Purpose</h3> Azole antifungals are CYP3A4 inhibitors known to significantly impact tacrolimus levels. Required tacrolimus dose reduction with azole initiation is well known; however, little is reported on empiric tacrolimus dose adjustments with azole discontinuation (d/c). We describe our experience with tacrolimus adjustment after d/c of posaconazole. <h3>Methods</h3> This is a retrospective single center review of heart transplant recipients who received 3 months of posaconazole prophylaxis immediately post-transplant. Upon d/c, our protocol increased total tacrolimus dose by 2-3 fold with level monitoring twice weekly for at least two weeks until at target. We analyzed the first 7 tacrolimus troughs and total daily doses (TDD) after d/c. Stable target levels post d/c were defined as first trough at goal with the TDD equivalent to doses at 3 months post d/c. Intrapatient tacrolimus level variability (IPV) was calculated using mean absolute deviation of dose corrected tacrolimus levels, with paired t test and descriptive statistics. <h3>Results</h3> Among 28 patients who received posaconazole from January 2020 to May 2021, average age was 55.5 years, 75% were male and 82% white. Tacrolimus TDD was significantly lower on posaconazole compared to 3 months post-d/c (0.02 vs 0.09 mg/kg/day, p = 0.0001). Analysis of target trough achievement is shown in Figure 1. Significant difference in IPV was noted between early (first 3) and late (next 4) levels, p=0.0004 (Figure 2). Median time to stable target levels was 21.5 (11-48) days. Four patients (14%) had 2R rejection within one month of d/c at which time median lowest tacrolimus level was 4.2 ng/mL (3.4-8.2 ng/mL). <h3>Conclusion</h3> Discontinuation of posaconazole leads to significant tacrolimus variability that can persist for weeks. A more conservative tacrolimus dose adjustment at time of d/c, with close monitoring throughout the first 3 weeks may be needed. Additional data is necessary to develop defined empiric dose adjustments for tacrolimus during this high-risk time.