Total Daily Dose Research Articles

МОНИТОРИНГ РАДИАЦИОННЫХ НАГРУЗОК И КОЭФФИЦИЕНТА КАЧЕСТВА ИОНИЗИРУЮЩЕГО КОСМИЧЕСКОГО ИЗЛУЧЕНИЯ В СЛУЖЕБНОМ МОДУЛЕ МКС С ИСПОЛЬЗОВАНИЕМ НАУЧНОЙ АППАРАТУРЫ «ТРИТЕЛЬ»

The paper reports the results of measuring absorbed doses and quality factor of ionizing space radiation in the ISS Service module in June-October of 2020 with the use of dosimeter Tritel as part of space experiment Matreshka-R. Mean dose rate over the period amounted to 0.38 ± 0.03 mGy/d. Experimental data on the dose rate dynamics allow to set aside contributions of Earth's radiation belts and galactic cosmic radiation in the total daily dose. The daily average quality factors made up 3.05 ± 0.16 for total dose, 1.6 ± 0.1 for Earth's radiation belts and 5.1 ± 0.3 for galactic space radiation.

Оценка эффективности применения отечественных биосимиляров инсулина для лечения сахарного диабета 1 типа у подростков

Aim: to assess the potential effect of switching from original insulins (lispro and glargine) to Russian biosimilars on glycemic control in adolescents with type 1 diabetes (T1D). Patients and Methods: this 24-week observational clinical trial enrolled 24 adolescents with T1D aged 12–15 (mean age 13.4±1.1 years), 13 boys (54.2%, mean age 13.1±1.1 years) and 11 girls (45.8%, mean age 13.0±0.9 years). Disease duration was 4.0±1.1 years in boys and 4.3±1.8 years in girls. Insulin therapy included original multiple daily injections (MDI) of insulins lispro and glargine. Patients were switched to biosimilars at a ratio of 1:1, doses were adjusted by the patients themselves. Blood sugar levels were measured by flash glucose monitoring (FGM). Time in the target range (TIR), time above the target range (TAR), time below the target range (TBR), and glycated hemoglobin (HbA1c) in the original insulin therapy and 3 and 6 months after switching to Russian biosimilars were evaluated. Results: three and six months after switching of T1D adolescents to Russian biosimilars, no clinically significant worsening of glycemic control parameters was reported, i.e., HbA1c (3 months) 7.6±1.1%, HbA1c (6 months) 7.5±0.9% (p>0.05), TIR (3 months) 65.1±10.6%, TIR (6 months) 66.5±10.7% (р>0.05), TAR (3 months) 26.8±10.9%, TAR (6 months) 25.5±11.1% (p>0.05), TBR (3 months) 8.1±4.3%, TBR (6 months) 7.9±4.5% (p>0,05). No significant differences in the parameters studied between boys and girls 3 and 6 months after therapy switching were reported. No significant changes in the total daily Insulin dose (TDI) were reported, i.e., TDI (3 months) 1.4±0.3 U/kg, TDI (6 months) 1.3±0.3 U/kg. Conclusion: Russian biosimilars of insulins lispro and glargine for T1D in adolescents are not associated with either an increase in TDI or worsening of glycemic control parameters, e.g., HbA1c, TIR, TAR, and TBR. KEYWORDS: type 1 diabetes, insulin, biosimilars, lispro, glargine, glycated hemoglobin, glycemic control, time in the range. FOR CITATION: Platonov V.V., Dubinina T.A., Patrakeeva E.M. et al. Efficacy of Russian insulin biosimilars for type 1 diabetes in adolescents. Russian Journal of Woman and Child Health. 2022;5(2):165–168 (in Russ.). DOI: 10.32364/2618-8430-2022-5-2-165-168.

Tip 1 Diabetes Mellitus'lu Çocuklarda Fiziksel Aktivite ve İlişkili Durumların Değerlendirilmesi: Kesitsel Bir Çalışma

Objective: This study was conducted to determine the physical activity level of children with Type 1 Diabetes Mellitus and to evaluate the conditions that may be associated with physical activity. Material and Methods: This cross-sectional study was conducted in the pediatric endocrinology outpatient clinic of a university hospital between September 1, 2018, and March 30, 2019. Data were collected through the Personal Information Form for Children and the Physical Activity Questionnaire for Children (PAQC). Data analysis included the Independent t-test, One-way Anova test, Pearson Correlation, and Linear Regression Model. Results: Results showed that the physical activity mean score of children with Type 1 Diabetes Mellitus (n=111) was 2.75±0.6, and the children had a moderate physical activity level. No statistically significant relationships were detected between hemoglobin A1c (HbA1c) levels, Body Mass Index values, daily TV viewing time, and PAQC averages of children with Type 1 Diabetes Mellitus. It was found that fathers'education level, adherence to medical nutrition therapy, regular physical activity, total daily insulin dose, and daily sleep duration were effective variables on the total PAQC averages. Regular physical activity, total daily insulin dose, and sleep duration were found to explain 26.6% of the PAQC averages. Conclusion: This study found that the total daily insulin dose and sleep duration decreased as the physical activity level increased. It was determined that there was no correlation between physical activity and HbA1c level.

Correlation Between Lacunae and the Wearing-off Phenomenon in Parkinson's Disease.

PurposeLacunae are imaging biomarkers of cerebral small vessel disease (CSVD) and are correlated with the degree of gait instability in Parkinson’s disease (PD). The wearing-off phenomenon (WO) occurs more frequently in PD patients as disease progresses. The present study aimed to investigate the overall impact of the quantity and location of lacunae on the WO in PD.Patients and MethodsThis retrospective, single-center study included 315 consecutive eligible patients with PD from Beijing Tiantan Hospital from May 2016 to August 2018. We collected data on demographics and clinical features, assessed lacunae and examined the presence of the WO. The association between lacunae and the WO was assessed using a binary logistic regression model.ResultsThe number of lacunae was significantly associated with the WO in patients with PD according to a model adjusted for age at onset, disease duration, Hoehn–Yahr (H-Y) staging, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) total score and levodopa equivalent daily dosage (LEED) (P=0.037, OR 1.156, 95% CI 1.009, 1.325) and to a model further adjusted for other CSVD imaging biomarkers (P=0.046, OR 1.172, 95% CI 1.003, 1.369). Following additional adjustment for other potential confounders, the association remained significant (P=0.043, OR 1.195, 95% CI 1.005, 1.421). Lacunae in subcortical areas (P=0.004, OR 0.498, 95% CI 0.308, 0.803) and basal ganglia (P=0.046, OR 1.616, 95% CI 1.009, 2.587), especially in the caudate nuclei (P=0.023, OR 1.104, 95% CI 0.185, 0.881), were significantly associated with the WO in PD patients.ConclusionOur finding highlights the significant association between lacune and the WO, and lacunae may be an independent contributor to the WO in PD patients. Promoting neurovascular health may prevent the progression of the WO in PD patients.

Impact of MDR1 and UGT Gene Polymorphisms on Sodium Valproate Plasma Concentration in Patients with Epilepsy.

This study aimed to identify the effects of multidrug resistance gene 1 (MDR1) and UGT gene polymorphisms on the plasma concentration of VPA in subjects with epilepsy and provide a reference for individualized medicine of patients with epilepsy. One hundred subjects with epilepsy who were treated with sustained release VPA monotherapy were enrolled. Sanger sequencing was used to detect the genotypes of MDR1_G1199A, MDR1_G2677T/A, UGT1A6_A 552C, T19G and UGT2B7_C161T. By adjusting the plasma concentrations of VPA with body weight and a total daily dose of VPA, the concentration-to-dose ratio of VPA (CDRV) was obtained. Data were analyzed using SPSS17.0. No mutation of MDR1_G1199A gene was detected. MDR1_G2677T/A site T allele frequency is 43.5%, A is 14%. The genetic frequencies of UGT1A6_A552C, T19G, and UGT2B7_C161T were 29.5%, 25.5%, and 36%, respectively. Significant differences in CDRV were observed between carriers of TT, TG, and GG genotypes in the UGT1A6_T19G polymorphism (p = 0.021, p < 0.05). The CDRV was significantly lower in patients carry UGT1A6_T19G GG genotype compared to TG ((3.40 ± 1.61) μg.kg/mL.mg) and TT ((4.33 ± 1.97) μg.kg/mL.mg) genotype. While the MDR1_G2677T/A, UGT1A6_A552C and UGT2B7_C161T gene polymorphisms had no effect on the plasma concentration of VPA (p > 0.05). The genetic polymorphisms of UGT1A6_T19G significantly affect the plasma concentration of VPA in patients with epilepsy and the mutation of this locus can decrease the blood concentration of VPA. The MDR1_G2677T/A, UGT1A6_A552C and UGT2B7_C161T gene polymorphisms did not affect the plasma VPA concentration in Han patients with epilepsy.

Management of Acute Adrenal Insufficiency-Related Adverse Events in Children with Congenital Adrenal Hyperplasia: Results of an International Survey of Specialist Centres.

There is wide variation in reported rates of acute adrenal insufficiency (AI)-related adverse events (sick day episodes and adrenal crises) between centres. This study aimed to evaluate the level of consensus on criteria considered essential for defining and managing these events in children with Congenital Adrenal Hyperplasia. Active users of the International Congenital Adrenal Hyperplasia and International Disorders of Sex Development (I-CAH/I-DSD) Registries (n = 66), non-active users of I-CAH/I-DSD (n = 35), and the EuRRECa e-Reporting Registry (n = 10) were approached to complete an online survey. Fifty-six centres from 27 countries responded to the survey; the response rates for the three groups were 42 (65%), 11 (31%), and 3 (30%), respectively. Steroid management plans, one to one patient education, and contact details of health care staff were provided by over 90% of centres in high-income countries. All 56 centres advised glucocorticoid stress dosing in the event of fever. Less common indications for sick day dosing included vaccination and mild afebrile intercurrent illness, recommended by 17 (30%) and 9 (16%) centres, respectively. The most frequently reported stress dosing regimens were tripling the total daily dose of hydrocortisone and administering 3 times daily and doubling or tripling the largest daily hydrocortisone dose depending on the nature of the trigger and administering 3 times daily, recommended by 24 (43%) and 21 (38%) centres, respectively. Vomiting was the most common indication for intramuscular hydrocortisone injection, reported by 34 (61%) centres. Over 50% of respondents indicated that essential clinical criteria for adrenal crisis should include fatigue and nausea or vomiting and over 60% indicated that hypotension, hyponatraemia, hyperkalaemia, and clinical improvement following parenteral glucocorticoids were essential criteria. In the event of an adrenal crisis, 47 (84%) reported that the majority of patients were admitted to hospital. For the management of an adrenal crisis, a bolus parenteral injection of hydrocortisone was the most frequently administered medication, reported by 50 (89%) centres. Although there is variation in the definition and management of AI-related adverse events in children amongst centres, there is also a good level of consensus on specific aspects that can lead to greater benchmarking of care.

Assessment-of-vancomycin-pharmacokinetic-parameters-among-malaysian-adult-patients-in-penang-with-different-kidney-functions

Introduction: Vancomycin is indicated for highly resistant gram-positive systemic infections. The targeted trough and 24-hour area under the concentration-time curve (AUC24) level of vancomycin must be achieved for efficacy and safety. Local population-based pharmacokinetic parameters including the elimination rate constant (Ke), half-life (t1/2), volume of distribution (Vd) and vancomycin clearance (Clvanco) can allow better vancomycin dosing determination. Objective: This study aims to determine the pharmacokinetic parameters in the Malaysian adult patients in Penang based on different kidney functions. Method: This was a retrospective, single-centered study conducted in the Clinical Pharmacokinetics Department, Penang General Hospital from 1 January 2016 to 31 December 2017. This study included adult patients who had been treated with intravenous vancomycin under therapeutic drug monitoring. The patients’ personalised vancomycin pharmacokinetic parameters were determined using a series of pharmacokinetic equations. Result: From the recruited 26 patients, 73.1% were male and 46.2% were above 50 years old. A total of 34.6% patients had the actual body weight / ideal body weight ratio of more than 1.0. The median total daily dose was 34.72 mg / kg. The median for Cmax (peak serum concentration) was 26.0 mg /L while Cmin (trough serum concentration) was 14.20 mg / L. The median for AUC24 is 412.08 mg*hr / L. The overall median for Ke and t1/2 were 0.091 hr-1 and 7.62 hours, respectively. The median Vd was 0.90 L / kg. It was found that with increasing creatinine clearance, the Ke and Vd increased while the t1/2 decreased. Conclusion: The vancomycin pharmacokinetic data from this study varied according to different degree of creatinine clearances.

Bone Age Maturation and Growth Outcomes in Young Children with CAH Treated with Hydrocortisone Suspension.

BackgroundYoung children with congenital adrenal hyperplasia (CAH) require small doses (0.1-1.25 mg) of hydrocortisone (HC) to control excess androgen production and avoid the negative effects of overtreatment. The smallest commercially available HC formulation, before the recent US Food and Drug Administration approval of HC granules, was a scored 5-mg tablet. The options to achieve small doses were limited to using a pharmacy-compounded suspension, which the CAH Clinical Practice Guidelines recommended against, or splitting tablets into quarters or eighths, or dissolving tablets into water.MethodsCross-sectional chart review of 130 children with classic CAH treated with tablets vs a pharmacy-compounded alcohol-free hydrocortisone suspension to compare growth, weight, skeletal maturation, total daily HC dose, and exposure over the first 4 years of life.ResultsNo significant differences were found in height, weight, or body mass index z-scores at 4 years, and in predicted adult height, before or after adjusting for age at diagnosis and sex. Bone age z-scores averaged 2.8 SDs lower for patients on HC suspension compared with HC tablets (P < 0.001) after adjusting for age at diagnosis and sex. The suspension group received 30.4% lower (P > 0.001) average cumulative HC doses by their fourth birthday.ConclusionsOur data indicate that treatment with alcohol-free HC suspension decreased androgen exposure as shown by lower bone age z-scores, allowed lower average and cumulative daily HC dose compared to HC tablets, and generated no significant differences in SDS in growth parameters in children with CAH at 4 years of age. Longitudinal studies of treating with smaller HC doses during childhood are needed.

Buprenorphine Dosing Frequency is not Associated with Maternal Stability and Neonatal Outcomes

Pregnancy alters pharmacokinetics for buprenorphine with variation in dosing suggested from the common once a day (QD) scheme outside pregnancy. Our objective was to determine the relationship between dosing frequency and maternal stability, as measured by rates of relapse and prenatal compliance, and neonatal abstinence syndrome (NAS) rates. This study was from a longitudinal cohort of women receiving care through the PATHways program between 2015 and 2021. We compared outcomes for enrollees prescribed twice a day (BID) or greater dosing of buprenorphine at delivery versus QD. Maternal compliance with treatment goals included inappropriate maternal UDS results, reported illicit use at prenatal appointments, and no-call, no-show visits. This score was the percentage meeting goals from all prescribed visits. Women not taking buprenorphine at delivery were excluded as well as those with less than 6 weeks duration of antepartum therapy. Fisher’s exact test was used for our statistical analysis. 284 patients were included, with 226 (79.5%) underwent QD dosing versus 58 dosed BID or TID. Demographics were similar between groups. Mean total dose per day was significantly higher in the BID/TID group (14.61 ± 5.3 vs 11.86 ± 5.01, P=0.003), see Table 1. When comparing dosing frequency subgroups, maternal compliance scores were not significantly different (0.54± 0.31 vs 0.55± 0.31, P=0.83). No difference was evident in the total antepartum visits attended per group. When neonatal outcomes were assessed, no differences between birthweight, gestational age at delivery, rates of NAS, NAS treatment duration, or neonatal length of stay, see Table 2. Dosing frequency of buprenorphine was related to total daily dose but was not associated with maternal stability or neonatal outcomes. The presence of equipoise for this clinical finding provides justification for a randomized trial to evaluate differences based on dosing frequency.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Delirium in a Tertiary Pediatric Cardiac Intensive Care Unit: Risk Factors and Outcomes.

Delirium is an increasingly recognized hospital complication associated with poorer outcomes in critically ill children. We aimed to evaluate risk factors for screening positive for delirium in children admitted to a pediatric cardiac intensive care unit (CICU) and to examine the association between duration of positive screening and in-hospital outcomes. Retrospective cohort study in a single-center quaternary pediatric hospital CICU evaluating children admitted from March 2014-October 2016 and screened for delirium using the Cornell Assessment of Pediatric Delirium. Statistical analysis used multivariable logistic and linear regression. Among 942 patients with screening data (98% of all admissions), 67% of patients screened positive for delirium. On univariate analysis, screening positive was associated with younger age, single ventricle anatomy, duration of mechanical ventilation, continuous renal replacement therapy, extracorporeal life support, and surgical complexity, as well as higher average total daily doses of benzodiazepines, opioids, and dexmedetomidine. On multivariable analysis, screening positive for delirium was independently associated with age <2 years, duration of mechanical ventilation, and greater than the median daily doses of benzodiazepine and opioid. In addition to these factors, duration of screening positive was also independently associated with higher STAT category (3-5) or medical admission, organ failure, acute kidney injury (AKI), and higher dexmedetomidine exposure. Duration of positive delirium screening was associated with both increased CICU and hospital length of stay (each additional day of positive screening was associated with a 3% longer CICU stay [95% CI = 1%-6%] and 2% longer hospital stay [95% CI = 0%-4%]). Screening positive for delirium is common in the pediatric CICU and is independently associated with prolonged intensive care unit (ICU) and hospital stay. Longer duration of mechanical ventilation and higher sedative doses are independent risk factors for screening positive for delirium. Efforts aimed at reducing these exposures may decrease the burden of delirium in this population.

Safe and effective use of a hybrid closed‐loop system from diagnosis in children under 18 months with type 1 diabetes

The management of type 1 diabetes in infancy presents significant challenges. Hybrid closed loop systems have been shown to be effective in a research setting and are now available for clinical use. There are relatively little reported data regarding their safety and efficacy in a real world clinical setting. We report two cases of very young children diagnosed with type 1 diabetes at ages 18 (Case 1) and 7 months (Case 2), who were commenced on hybrid closed-loop insulin delivery using the CamAPS FX™ system from diagnosis. At diagnosis, total daily dose (TDD) was 6 and 3.3 units for Case 1 and 2, respectively. Closed loop was started during the inpatient stay and weekly follow up was provided via video call on discharge. Seven months from diagnosis, Case 1 has an HbA1C of 49 mmol/mol, 61% time in range (TIR, 3.9-10 mmol/L) with 2% time in hypoglycemia (<3.9 mmol/L) with no incidents of very low blood glucose (BG; <3 mmol/L, 54 mg/dL) over 6 months. Given the extremely small TDD of insulin in Case 2, we elected to use diluted insulin (insulin aspart injection, NovoLog, Novo Nordisk Inc., Plainsboro, NJ, Diluting Medium for NovoLog®). Six months from diagnosis, the estimated HbA1c is 50 mmol/mol, TIR 76% with 1% hypoglycemia and no incidents of very low BG (<3 mmol/L, 54 mg/dL) over 6 months. We conclude that the use hybrid closed-loop can be safe and effective from diagnosis in children under 2 years of age with type 1 diabetes.

Comparison of antimicrobial dosing recommendations in patients receiving intermittent hemodialysis among drug information resources.

Tertiary drug information resources are frequently consulted for the optimal antimicrobial dosing in intermittent hemodialysis (IHD) patients. Yet, significant discrepancy may exist in dosing recommendations between resources. This study was to evaluate the consistency of antimicrobial dosing recommendations in IHD among four different drug information resources and the relevance of referenced pharmacokinetic studies. Dosing recommendations of 29 commonly prescribed antimicrobials in IHD patients were collected from Micromedex, LexiComp, Clinical Pharmacology and Drug Prescribing in Renal Impairment to compare dosing categorization and the total daily dose (TDD). Significant dosing discrepancies were defined as ≥30% difference. Referenced pharmacokinetic studies were evaluated for their relevance in current practice, using sample size, hemodialyzer types, the use of optimal pharmacodynamic targets and the consideration of different interdialytic dosing periods. A significant variation was found both in dosing categorization and recommended doses between resources. Seventeen drugs were compared for TDD with significant dosing discrepancy in 8 drugs. Among 42 referenced pharmacokinetic studies, 40 were evaluated. Mean patient numbers of pharmacokinetic studies were 13 ranging from 3 to 70. Sixty per cent of studies utilized contemporary hemodialyzers (e.g., high-flux and/or high efficiency). The optimal pharmacodynamic targets and the impact of different interdialytic intervals were assessed only in 27.5% and 7.5% respectively. Inconsistent antimicrobial dosing recommendations for IHD patients exist among four well-established resources. Many referenced pharmacokinetic studies utilized outdated or less pharmacodynamically relevant study methods. Newer studies are warranted to reflect contemporary dialysis practice and assess its impact on optimal antimicrobial dosing.

1108. Evaluation of Vancomycin Dosing in Adolescents

BackgroundPediatric vancomycin dosing varies based on age and renal function. Recent literature suggests previously recommended doses of 45-60 mg/kg/day may be insufficient to achieve an AUC:MIC ratio of 400-600 mg-hr/L and higher doses of at least 60 mg/kg/day may be required. However, data to guide dosing in adolescents is limited. MethodsA single-center, retrospective chart review of patients aged 12 to 18 years who received vancomycin and had therapeutic drug monitoring (TDM) performed between July 2017 to June 2020 were included. The primary endpoint was the median total daily dose (TDD) of vancomycin required to achieve therapeutic serum concentrations. Secondary endpoints were to characterize how factors such as age, weight, trough versus AUC monitoring, malignancy, and trauma may influence dosing. The safety endpoint was the development of acute kidney injury (AKI).Results130 vancomycin courses in 86 patients were included. Baseline characteristics are presented in Table 1. Of the 130 vancomycin courses, 50 courses (38%) achieved therapeutic serum concentrations at a median TDD of 49.8 mg/kg/day (IQR 42 – 59.4). This was not statistically different from the sub- or supra-therapeutic groups (p=0.22). Based on age, the median TDD for 12-14 year olds was higher at 60 mg/kg/day (IQR 45-78.8; n=14) than for 15-16 and 17-18 year olds [45.3 mg/kg/day (IQR 41.1-51; n=15), 48 mg/kg/day (IQR 42-52; n=21), respectively]. Obese patients needed a median TDD of 43.5 mg/kg/day vs at least 51 mg/kg/day in healthy and overweight patients. Finally, AUC guided dosing resulted in a slightly lower overall median TDD vs trough guided dosing (45.8 mg/kg/day vs 50.5 mg/kg/day). Additional dose requirements based on age, weight, TDM and other characteristics are presented in Table 2. Of the 15 patients who developed AKI per pRIFILE criteria, 2 were classified as injury and 3 as failure.Table 2. Total Daily Dose Course Analysis ConclusionTo achieve therapeutic levels, adolescents 12 to14 years old need higher empiric doses of 60 mg/kg/day compared to 45 mg/kg/day in 15 to 18 year olds. Obese patients, however, may require lower TDD than underweight, healthy, and overweight patients. Patients that receive AUC versus trough monitoring may also require lower TDD to achieve therapeutic concentrations. More data is needed to further evaluate our findings.Disclosures All Authors: No reported disclosures

1103. Minocycline (MIN) Pharmacodynamics (PD) against Stenotrophomonas maltophilia (STM) in a Neutropenic Murine Thigh Infection Model

BackgroundAntibiotic treatment options for serious STM infections are limited. MIN displays in vitro activity against STM; however, limited data supports optimal dosing for STM. Herein, we employed the murine neutropenic thigh infection model to assess MIN PD against STM.MethodsFour clinical STM isolates with MIN MICs 0.25 – 1 mg/L were included. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Mice received uranyl nitrate on Day -3 to provide predictable renal impairment. Two hours after inoculation, MIN or control was administered subcutaneously. Pharmacokinetic (PK) studies of 2.5, 25, 50, and 100 mg/kg were conducted. Previously reported protein binding of 78.1% was used to define free exposure. Dose ranging studies were conducted on all STM to assess in vivo activity over a range of MIN exposures. MIN total daily doses (TDD) of 10, 20, and 50 mg/kg were fractionated q24h, q12h, and q6h against a single STM to determine the PD index best correlated with reductions in CFU/mL. Efficacy was measured in log10CFU/thigh at 24h compared with 0h controls. Composite CFU data were fitted to an Emax model to determine the fAUC/MIC exposure for stasis and 1 log10 reduction.ResultsMIN PK was linear up to 50 mg/kg and well described by a 1 compartment model with first order absorption and elimination. Mean PK parameters across the linear range were: Vd, 2.97 L/kg; K01, 10.62 1/h; and K10, 0.35 1/h. Mean ± SD bacterial burden at 0h across all isolates was 6.17±0.20 log10CFU/thigh. In 24h controls, bacterial growth was 7.90±0.85 log10CFU/thigh. A dose response was observed across all isolates using TDD of 2-300 mg/kg. PD indices correlated with CFU reductions as follows: fAUC/MIC (R2=0.613), fCmax/MIC (R2=0.590), and %fT >MIC (R2=0.504). The fAUC/MIC needed for stasis and 1 log10 reduction at 24h was 9.6 and 23.6, respectively. ConclusionThese are the first data describing MIN PD against STM. Against these STM, MIN fAUC/MIC was the PD index best correlated with CFU reductions. The exposure thresholds defined in this study will be useful in designing optimal MIN dosing regimens for treating STM infections and re-assessment of the current susceptibility breakpoint. The study was funded under FDA Contract 75F40120C00171.Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

1091. Validation of an Allometrically Scaled Body Weight Equation to Predict Vancomycin Clearance and Guide 24-Hour Vancomycin AUC Dosing in Obese Patients

BackgroundAccurately determining empiric vancomycin (VAN) doses in obese patients represents a clinical challenge. A recent population pharmacokinetic (PK) study provided an equation to estimate vancomycin clearance (CL) based on age, sex, serum creatinine (Scr), and allometrically scaled body weight. The purpose of this study was to validate this equation in a population of obese adults treated with vancomycin at eight community-based hospitals and use the CL estimate to guide empiric VAN dosing. MethodsThe study period was November 1, 2020 and March 30, 2021. Patients were included if they were ≥ 18-year-old with a body mass index (BMI) ≥ 30 kg/m2, had an empiric dose targeting an AUC24 determined using the above referenced equation, and had a calculated AUC24. Only the first vancomycin course and AUC calculation for each patient were included. Patients with a creatinine clearance < 30ml/min and pregnant women were excluded. AUC24 and other PK parameters were calculated using two levels and noncompartmental analysis. Observed versus predicted CL and AUC24 were plotted to determine correlation. ResultsSixty patients were included, of which 60% were male and 33% had a confirmed methicillin-resistant Staphylococcus aureus infection. The mean age, BMI, and baseline Scr were 61.8 years, 37.8 kg/m2, and 0.99 mg/dL, respectively. Fifty-three (88%) patients received a loading dose, with a mean dose of 20.3mg/kg. The mean initial total daily maintenance dose was 2397.9mg. The mean predicted AUC24 was 476.4mg*h/L while the mean observed AUC24 was 556.3mg*h/L. For CL, the correlation between observed and predicted values was R2=0.38 (Figure 1). The correlation between predicted and observed AUC24 values was R2=0.08 (Figure 2). The percent of patients with observed AUC24 values of < 400mg*h/L, 400-600mg*h/L, and >600mg*h/L were 23%, 40%, and 37%, respectively. The relationship between calculated minimum concentrations (Cmin) and AUC24 is shown in Figure 3. 65% of patients with a therapeutic AUC achieved it with a Cmin < 15mg/L while 4.5% of patients with a supratherapeutic AUC had a Cmin < 15mg/L. Figure 1. Observed versus Predicted Clearance (CL) of Vancomycin Figure 2. Observered versus Predicted 24 hour Vancomycin Area Under the Curve (AUC24) Figure 3. Calculated 24 hour Vancomycin Area Under the Curve (AUC24) versus Calculated minimal concentration (Cmin) ConclusionThe correlation between observed and predicted CL was 0.38. Using these CL estimates to guide empiric VAN dosing resulted in only 40% of patients achieving a therapeutic AUC24. Disclosures All Authors: No reported disclosures

1102. Evaluation of Vancomycin Accumulation in Patients with Obesity

BackgroundCurrent vancomycin guidelines recommend using actual body weight for dosing. However, in patients with obesity, this may result in lower initial vancomycin concentrations that can accumulate with continued doses due to differences in volume of distribution. The objective of this study is to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation.MethodsThis is a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a BMI ≥ 30 kg/m2 and with ≥ 2 vancomycin serum trough concentrations within the same encounter in 2019 were screened. Patients were excluded if they were pregnant, had unstable renal function or severe renal impairment, received < 3 doses before a concentration was drawn, or had inconsistent dosing prior to a concentration draw. Linear kinetics were used to correct for differences in timing of concentration or dose changes. The major endpoint was the incidence of vancomycin accumulation, defined as a 20% increase in trough concentration between the first and any subsequent trough concentrations within the first 10 days of therapy. Minor endpoints included the percentage of supratherapeutic concentrations and the incidence of acute kidney injury (AKI). Descriptive statistics were used to evaluate endpoints and multivariable logistic regression was used to evaluate factors associated with accumulation.ResultsWe screened 543 patients, and 162 were included in our analysis. The median age was 56.5 years (interquartile range [IQR] 43 - 65.3), and 62.3% were male. The median weight was 112.7 kg (IQR 99.8 - 122.6) and the median BMI was 36.8 kg/m2 (IQR 33.1 - 41). The median total daily vancomycin dose at initiation was 28.7 mg/kg/day (IQR 25.4 - 31.2). Vancomycin accumulation occurred in 99 patients (61.1%) within the first 10 days of therapy and AKI occurred in 21 patients (14.9%). No factors studied, including age, gender, obesity class, initial dose, SCr, or frequency were associated with accumulation.ConclusionMost patients with obesity experienced vancomycin accumulation within the first 10 days of therapy. Providers should be cautious when assessing a vancomycin concentration early in the treatment course.Disclosures All Authors: No reported disclosures

Clinical Impact of GLP-1 receptor agonists in veterans receiving basal-bolus insulin.

In 2017, an estimated 7.4million Americans used insulin to treat diabetes. Insulin is proven to lower A1c but can result in hypoglycemia and weight gain. Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1-RA) may provide additional blood glucose control while limiting undesirable effects including weight gain. To characterize the clinical impact of adding a GLP-1-RA to a basal-bolus insulin regimen in patients with type 2 diabetes. This retrospective observational study used national Veteran's Health Administration data to identify patients with an existing basal-bolus insulin regimen who initiated a GLP-1-RA between January 1, 2005 and December 31, 2017. A1c, insulin total daily dose (TDD), and weight were collected at GLP-1-RA initiation (baseline), 3-, 6-, and 12-month time points and then analyzed using an intent-to-treat approach with the last observation carried forward. Decreases in A1c ≥ 0.5% and weight ≥2kg were deemed clinically significant. Among 7651 patients initiating GLP-1-RA therapy, mean A1c had a clinically significant decline at 3, 6, and 12months by -0.5%, -0.7%, and -0.7%, respectively, from a mean baseline of 9%. Patients with lower baseline A1c levels did not have clinically significant changes in A1c, whereas patients with baseline A1c ≥9% had more clinically significant declines. Insulin TDD decreased by -32, -38, and -42 units/day at 3, 6, and 12months, respectively, where the mean decrease in insulin TDD at 12months was 79 units/day among patients who discontinued bolus insulin (52.3%) compared with a mean decrease of 2 units/day among those who continued bolus insulin. Mean weight reductions at 3, 6, and 12months were -1.2, -2.3, and -2.9kg, respectively, from a mean baseline of 120.6kg. Combining a GLP-1-RA with basal-bolus insulin had a clinically significant improvement on blood glucose control, lowered insulin TDD, and reduced weight. These outcomes were achieved within 3 to 6months following GLP-1-RA initiation and were maintained through 1year.

AACE2021-A-1087: Prevalence of Celiac Disease in Saudi Patients with Type 1 Diabetes Mellitus

The objective of our study is to determine the prevalence of celiac disease (CD) in adolescents and adults with type 1 diabetes mellitus (T1DM) using anti-tissue transglutaminase (anti-tTG) antibodies and/or endoscope, This study is a chart review retrospective study involving all adolescents and adults with T1DM who were screened for CD at king Abdulaziz medical city Riyadh between 2010 and 2019. The sample size was calculated to be 537 patients based on estimated prevalence of 10% of celiac disease. The study sample wad randomly selected from all patients diagnosed with T1DM and who had CD screening test in the institution. The software SPSSv22 was used for the sample selection. The study variables include age, sex, age of diagnosis with T1DM, age of positive celiac screening, glycated hemoglobin HBA1c, total daily dose, diabetes ketoacidosis (DKA) frequency and other autoimmune diseases. Ethical approval was obtained by ethical board committee with study number: RC19/295/R. A total 539 patients’ records were reviewed. The prevalence of positive celiac screening in our sample is 11.5% ( 4.1% males and 7.4% females). CD prevalence based on positive screening test was equal (5.7%)in young patients (age groups 10-19 years) and older patients (age group 19-65 years). About 8% of positive CD patients in this study diagnosed with T1DM after documented positive celiac screening test. Moreover; around 16% of them developed T1DM and screened positive at the same year. The rest of the patients were found to have positive CD screening after they were diagnosed with T1DM. Regarding A1C, 69.35% of positive screened celiac patients had A1C level between 7-10%. The rest of the patients with positive CD screening had their A1C level of > 10 and represents around 24% and only 6.45% have A1C less than 7%. Around 51% of the patients with CD positive screening never had DKA. The amount of total daily dose was significantly lower in positive CD patients compared to negative CD patients. There was no statistical significant difference between patients with CD screening positive or negative regarding A1C, microvascular complication of diabetes or thyroid disorder. Regarding histopathological confirmation of CD; only 37% Of those screened positive underwent endoscopy; of which 43% were found to have normal endoscopic biopsy findings, 21.7% found to have partial villous atrophy and 34.7% were found to have total villous atrophy. This study highlighted the importance of screening for CD in T1DM patients. CD prevalence is significantly high in patients with T1DM despite the likelihood of under diagnosis of the problem. Additional Saudi studies with different age groups and methods are required. In addition, a unified national strategy to diagnose CD in T1DM patients is highly advisable.

Methadone Switching for Cancer Pain: A New Classification of Initiation Protocols, Based on a Critical Literature Review

Background: The initiation of methadone, a known effective analgesic for cancer pain, is complex. The existing protocols are often inadequately described; therefore, a classification of literature is needed. We reviewed and classified the recent literature on methadone initiation protocols in cancer patients experiencing severe pain. Objective: To provide a new classification of initiation protocols, based on a critical literature review. Data Sources: The MEDLINE database was searched for articles published until March 25, 2021, using the terms "cancer pain," "methadone," "methadone introduction," or "methadone initiation." The search was limited to human studies, randomized controlled trials (RCTs), other clinical trials, meta-analyses, and case reports. Selected articles were assessed for initiation details (rapid or progressive), administered dose (fixed rescue dose or ad libitum), and dose calculation (fixed or progressive ratios using morphine equivalent daily dose [MEDD] for daily or unitary dose). Results: Twenty-four publications that met our inclusion criteria were analyzed. No large-scale prospective double-blind RCTs with robust design were identified. Most studies assessed relatively small numbers of patients. Eight initiation types were identified, of which three involved seven "high quality" studies: "rapid switch-fixed doses and rescue dose-progressive daily ratio," "progressive switch-fixed dose and rescue dose-progressive daily ratio," and "rapid switch-ad libitum-fixed ratio for unitary dose" protocols. This classification provides the latest information on methadone initiation protocols. The total daily dose of methadone varied largely across protocols. Conclusion: We recommend a maximal daily methadone dose of 100 mg (3 doses of 30 mg or 5 doses of 20 mg) for MEDD <500 mg, when the two "ad libitum" protocols are used. Further clinical research on this topic is warranted.

Abstract P02-02: First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy &amp;gt;85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in &amp;gt;20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.