Mean Plasma Research Articles

Hematological and plasma biochemical profile of two species of freshwater stingrays from the Amazon.

The evaluation of hematological and plasma biochemical parameters and the subsequent establishment of reference intervals facilitate the diagnosis of the health status of animals. This work aimed to determine the blood parameters of wild specimens of the stingrays Potamotrygon motoro and Potamotrygon orbignyi from the lower Solimões River region, Amazonas, Brazil. One hundred forty-one stingrays were captured, 92 specimens of P. motoro and 49 of P. orbignyi, of both sexes and at different stages of development. No effect of sex was observed on the blood parameters of juvenile animals for both species. P. motoro neonates presented a distinct hematological and biochemical profile, with significantly lower hematocrit values, hemoglobina, number of erythrocytes, mean corpuscular hemoglobin concentration, monocytes, plasma glucose, total proteins, albumin, and globulin. On the other hand, total cholesterol and urea levels were significantly higher in this same group compared to juveniles of the same species. Comparison between species revealed lower values of triglycerides and total cholesterol in P. orbignyi of both sexes. The results obtained are pioneering for these Amazonian species in white water environments and will serve as a basis for evaluating the health status of wild stingrays. Thus, from the analysis of the blood of the P. motoro and P. orbignyi stingrays, it was possible to observe good health conditions.

Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

To conduct a thorough pharmacokinetic (PK)- pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB). Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software. A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population. The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults.

Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax). Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1h post-injection. This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (equal to or less than 45 vs. older than 45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p = 0.6388), but higher than the unhealthy group (p < 0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p = 0.7819) and lower than the healthy group (p = 0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: A double-blind first-in-human study.

Rusfertide is a potent peptide mimetic of hepcidin being investigated for the treatment of polycythemia vera. This randomized, placebo-controlled, double-blind study evaluated the safety, pharmacokinetics, and pharmacodynamics of single and repeated subcutaneous doses of an aqueous formulation of rusfertide in healthy adult males. Subjects received single doses of 1, 3, 10, 20, 40, or 80 mg rusfertide or placebo. A separate cohort of subjects received two doses of 40 mg rusfertide or placebo 1 week apart. Blood samples for pharmacokinetics and pharmacodynamics were collected, and adverse events, clinical laboratory tests, 12-lead electrocardiograms, and vital signs were monitored. Rusfertide was well tolerated. There were no serious or severe treatment-emergent adverse events, and no patterns of clinically important adverse events, or laboratory, vital sign, or electrocardiogram abnormalities. Mean maximum rusfertide plasma concentration (Cmax) and area under the concentration-time curve increased with dose, but less than dose proportionally. Median time to Cmax was 2-4.5 h for 40 and 80 mg rusfertide and 8-24 h for lower doses. Apparent clearance and half-life increased with dose. Single doses of rusfertide 1-80 mg were associated with dose-dependent decreases in serum iron and transferrin-iron saturation. Rusfertide was well tolerated and showed dose-dependent pharmacokinetics and pharmacodynamics.

#2707 Prediction of plasma sodium changes in hypernatremic patients: the role of tissue sodium content

Abstract Background and Aims Hypo- and hypernatremia are frequently encountered electrolyte disturbances in clinical practice. Rapid correction of these dysnatremias can result in severe neurological complications. Therefore, various formulas have been developed to predict changes in plasma sodium concentration ([Na+]) after treatment. However, these kidney-centered formulas have been shown to be inaccurate. A potential explanation for the discrepancy between predicted and measured plasma [Na+] is the accumulation of sodium in the skin, which is not explicitly taken into account in these formulas. The purpose of this post-hoc analysis is to evaluate the association between factors related to tissue sodium accumulation and the discrepancy between measured and predicted plasma [Na+]. Method We used data from a hypernatremic intensive care unit (ICU) cohort with 66 patients and 1,034 ICU days with complete data on sodium, potassium and water balance. We excluded ICU days with incomplete balances, dialysis and severe diarrhea. The predicted plasma [Na+] was calculated using the Barsoum-Levine (BL) and the Nguyen-Kurtz (NK) formula. Then, we calculated the discrepancy between predicted and measured plasma [Na+] (∆[Na+]). We fitted a linear mixed-effect model to investigate the association between factors related to tissue sodium content and ∆[Na+]. Age, sex, blood pressure, eGFR, CRP, plasma albumin, total body water (TBW), baseline plasma [Na+] and changes in plasma [Na+] were incorporated as fixed effects in the model, while the subjects were introduced as a random effect. TBW was estimated as 60% of body weight for males and 50% of body weight for females, corrected for fluid balances on subsequent ICU days. Results A total of 613 ICU days of 66 patients were included in our analysis. The mean age was 58 ± 15 years and 38% was female. The mean plasma [Na+] at inclusion day was 145 ± 9 mmol/L and mean eGFR CKD-EPI was 52 ± 28 ml/min/1.73 m2. On average, the deviation between predicted and measured plasma [Na+] was 3.8 ± 3.3 mmol/L for the BL formula and 3.9 ± 3.4 mmol/L for the NK formula. For both formulas, TBW (p = 0.01), baseline plasma [Na+] (p &amp;lt; 0.001) and plasma [Na+] change (p &amp;lt; 0.001) were significantly associated with the discrepancy between predicted and measured plasma [Na+] (Table 1). Plasma albumin (p = 0.02) was also significantly associated with this discrepancy when the NK formula was used. Conclusion In a hypernatremic ICU cohort, baseline plasma [Na+], estimated TBW and plasma [Na+] changes are associated with the inaccurateness of plasma [Na+] prediction. As baseline plasma [Na+] and estimated TBW are available when initiating treatment, incorporation of these variables in the currently available formulas may improve the prediction of plasma [Na+].

#190 Long-term treatment with lumasiran: final results from the phase 2 open-label extension study

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder in which hepatic oxalate overproduction can lead to kidney failure and life-threatening systemic disease. Lumasiran, an RNA interference (RNAi) therapeutic indicated for treatment of PH1 to lower urinary oxalate (UOx) and plasma oxalate (POx) levels, reduces hepatic oxalate production by degrading the mRNA encoding glycolate oxidase. Patients with PH1 who completed a Phase 1/2 study were eligible to enroll in a Phase 2 open-label extension (OLE) study (NCT03350451) within 12 months of completing the Phase 1/2 study. Method Patients enrolled in the 54-month Phase 2 OLE had previously met eligibility criteria for the Phase 1/2 study, including: age 6 to 64 years, PH1 confirmed by genetic criteria, 24-hour (24 h) UOx excretion &amp;gt;0.7 mmol/1.73 m2/day, estimated glomerular filtration rate (eGFR) &amp;gt;45 mL/min/1.73 m2, and a stable pyridoxine (vitamin B6) regimen for patients taking vitamin B6. In the Phase 2 OLE, patients were to initiate subcutaneous lumasiran 1.0 mg/kg once monthly (qM), 3.0 mg/kg qM, or 3.0 mg/kg every 3 months (q3M) based on their dose/regimen in the Phase 1/2 study. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were change in 24 h UOx corrected for body surface area (BSA) over time, change in 24 h UOx:creatinine ratio (UOx:Cr) over time, and change in estimated glomerular filtration rate (eGFR) over time. Change over time in POx and plasma glycolate, incidence of anti-drug antibodies (ADAs), and rates of kidney stone AEs were also assessed. Results All 20 patients (median age 11.5 years; 65% female) who completed the Phase 1/2 study entered the Phase 2 OLE (Table 1). Most patients (65%) were taking vitamin B6 at baseline. All patients transitioned to the 3.0 mg/kg q3M dose/regimen by month (M) 21, and all patients completed the study. Six patients transitioned to commercially available lumasiran prior to M54 but on or after M45. The most common treatment-related AEs were injection-site reactions (ISRs) with 13 events in 8 patients (40%); all ISRs were graded mild. Of all lumasiran doses administered during the OLE, 3% (13 of 427 total doses of lumasiran) were associated with ISRs. Other than ISRs, the only treatment-related AEs affecting &amp;gt;1 patient were increases in bilirubin (N=3 patients; 15%); all events resolved without lumasiran dosing changes. Severe AEs were reported by 2 patients (10%); serious AEs were reported by 7 patients (35%). No deaths occurred. No severe or serious AEs were related to treatment, and no patients discontinued lumasiran or withdrew due to AEs. Lumasiran treatment led to a substantial reduction in 24 h UOx relative to the Phase 1/2 study-derived baseline (Fig. 1A). At M54, the mean absolute change from baseline in 24 h UOx was −1.5 mmol/24 h/1.73 m2 and the mean percent change was −68%. From M42 through M54, 24 h UOx was ≤1.5×ULN in ≥89% of patients. At M54, the mean percent change from baseline in 24 h UOx:Cr was −77%. Mean eGFR was generally stable over time (Fig. 1B). Mean absolute change from baseline in eGFR at M54 was −1.6 mL/min/1.73 m2. Lumasiran treatment also led to reductions in POx from baseline, and mean post-baseline POx values remained within the normal range through M54. Mean plasma glycolate levels were elevated at the start of the Phase 2 OLE due to persistence of the treatment effect from the Phase 1/2 study. After treatment resumed, levels increased and then plateaued. One patient (5%) had an ADA positive result at M6 but no ADA-related AEs; subsequent tests were negative through M48. Overall, the kidney stone AE rate was low during the Phase 2 OLE (0.17/person-year (PY]); by comparison, the rate of symptomatic kidney stones was 0.45/PY during the 12 months prior to the Phase 1/2 study and the kidney stone AE rate was 0.90/PY during the Phase 1/2 study. Conclusion In the longest follow-up reported to date, lumasiran treatment was well tolerated in patients with PH1 in the Phase 2 OLE. The most common treatment-related AEs were mild, transient ISRs; no severe or serious AEs were treatment related. Mean 24 h UOx reductions were sustained over more than 4.5 years of treatment. Mean eGFR was stable over time.

#2158 Circulating kidney injury molecule-1 a valuable marker of mortality in hemodialysis patients?

Abstract Background and Aims The importance of finding reliable biomarkers of mortality in CKD, and especially in patients treated with hemodialysis has become evident. Plasma KIM-1 has been mentioned as a marker of cardiovascular morbidity.. The aim of this study is to assess the level of plasma Kidney Injury Molecule- 1 (KIM-1) as a marker of mortality in patients treated with hemodialysis. Method We conducted a single-center study that included 63 CKD G5D patients (hemodialysis for 1-5 years) followed up for 48 months and a control group consisting of 52 patients diagnosed with CKD stages G1-G5, without HfrEF. All patients have been assessed at baseline, regarding cardiovascular disease (medical history, echocardiography and ECG). Circulating plasma KIM-1 levels were determined with single molecule counting immunoassay technology using the Enzyme-linked immunosorbent assay, we performed using standard methods blood biochemistry, and markers of inflammation (CRP, IL-6) and markers of anemia (complete blood count, serum ferritin, transferrin saturation- TSAT). Results Mean plasma KIM1 levels were 403.8 +/-546.8pg/ml) in the group of patients treated with hemodialysis, and was statistically significantly higher compared to the level in the control group (217.48 +/-267.10 pg/ml). In the group of patients treated with hemodialysis plasma KIM-1 levels showed a statistically significant correlation with inflammation (mean CRP- R=0.28, p=0.02 and IL6- R=0.36, p=0.005) and with anemia (hematocrit- R= -0.5, p=-0,0316; hemoglobin - R= -0.5, p=0.02 We found out using ANOVA that patients which presented left ventricular hypertrophy on echocardiography (37 out of 62) had significantly lower mean levels of plasma KIM-1 (155,51 vs 432,12 pg/ml; p=0,026). The group of patients with vascular calcifications on echocardiography (48 out of 62) had lower levels of serum KIM1 (210.01 vs 462.58 pg/ml, p=0.04). After 24 months of follow up we found a mortality rate of 22.23%, while after 48 months the mortality rate was of 50.73%. Using a Cox proportion-hazards regression analysis of predicting factors of mortality we found that regarding the relationship between plasma levels of KIM-1 and mortality there is a significantly decreased survival in patients with low KIM-1&amp;lt;81.98 pg/ml (p&amp;lt;0.001), with a cut-off point for plasma KIM-1 levels= 81.98 pg/ml. Conclusion Plasma KIM-1 levels were significantly higher in patients treated with hemodialysis compared to the control group (ND CKD patients). However, surprisingly, low levels of plasma KIM1 were associated with some cardiovascular changes and also to an increased risk of mortality (at 4 years, not after few months).

#2936 Chronic kidney disease in systemic sclerosis

Abstract Background and Aims Systemic sclerosis is a heterogeneous autoimmune disease with multiorgan involvement. To assess the clinical and epidemiological manifestations of patients with SSc who present CKD, and its implication in the prognosis and its importance in early detection. Method Selected 102 Caucasian patients (12 men and 90 women) diagnosed with SSc who were seen consecutively in the Scleroderma Unit at Vall d'Hebron Hospital since 1980. The following demographic variables were collected: sex, age, common cardiovascular risk factors (diabetes mellitus, hypertension, dyslipidemia), age at clinical onset, age at diagnosis, skin subtype of SSc according to the LeRoy and Medsger classification, visceral conditions, osteoarticular conditions, capillaroscopic pattern, biochemical parameters of renal function and immunological alterations, renal morphological alterations by ultrasound, and treatments. Results Overall, 102 SSc patients were included, of whom 24 (23.5%) had renal failure. The mean plasma creatinine value was 0.92 mg/dl and the mean GFR by CKD-EPI was 74.80 ml/min. The 76.5% had GFRe ≥60 ml/min (SScCKD-), with mean serum creatinine 0.85 ± 0.17 mg/dl and mean GFRe 82.13 ml/min (SD 20.53 ml/min); 23.5% had GFRe &amp;lt;60 ml/min (SScCKD+), in them mean serum creatinine was 1.09 ± 0.15 mg/dl and mean GFRe was 51.29 ml/min (SD 6.68 ml/min). By stage: 18 patients had G1 stage, 60 patients had G2 stage, 18 patients had GFR 3a and 6 patients GFR G3b. No proteinuria or hematuria was detected in any of the patients. In univariate analysis, limited cutaneous subtype was significantly more frequent in the SScCKD+ group (20, 83.3% vs. 44, 56.4%, p = 0.017) and the diffuse cutaneous subtype was more frequent in the SScCKD- group (0, 0% vs. 23, 29.4%, p &amp;lt; 0.001). In the study of associated antibodies, ACAs (20, 83.3% vs. 36, 46.1%, p = 0.001) were statistically significantly more frequent in the SScCKD+ group. No ATA were detected in SScCKD+ patients while in the SScCKD- group 25.6% had ATA (p = 0.003). Pulmonary involvement in the form of PAH was significantly more frequent in the SScCKD+ group (13, 54.1% vs. 19, 24.3%, p&amp;lt; 0.05). In pulmonary involvement in the form of ILD no differences were found (9, 37.5% vs. 37, 47.4% in SScCKD+ and SScCKD- patients, respectively). Regarding PFR results, there were no differences in the percentage of patients with FVC below 70% or 50% of the expected value (6, 25% vs. 15, 19.2% and 1, 4.1% vs. 4, 5.1%, respectively). Significant differences were found in mortality in the two groups (12, 50% vs. 16, 20.5%, in the SScCKD+ and SScCKD- group, respectively, p &amp;lt; 0.05), but not in the causes of death. Conclusion The presence of CKD in SSc conferred a clinical profile and prognosis.

#636 A phase 4, open label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease

Abstract Background and Aims Fabry disease (FD) is a rare inherited lysosomal storage disease caused by pathogenic GLA gene variants which result in a deficiency of the enzymatic activity of α-galactosidase A. Enzyme replacement therapy (ERT) is the mainstay of FD-specific treatment, but there are currently no reported clinical trials of ERT for FD in the Chinese population. This is the first phase 4 study to evaluate the safety and efficacy of ERT for FD in China since the approval of agalsidase beta in China in 2019. Method A 54-week, phase 4, open label, single arm, prospective, post-marketing surveillance (PMS) study of agalsidase beta (NCT05054387) was performed at 6 sites in China. Twenty-two Chinese ERT-naïve FD participants (≥8 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled and received infusions of agalsidase beta (Fabrazyme®, Sanofi) at a dose of 1.0 mg/kg every 2 weeks for up to 48 weeks. The primary endpoint was safety and tolerability of agalsidase beta. The endpoints of clinical efficacy included the changes of plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), FD symptoms (including angiokeratoma, hypohidrosis, anhidrosis, abdominal pain, headache, tinnitus, heat tolerance, and activity tolerance), and eGFR from baseline to week 48. A post-hoc subgroup analysis was conducted to explore the differences in ERT efficacy between two subgroups of different ages (&amp;lt;30 years and ≥30 years). Results All 22 patients completed the study intervention. There were 18 males (81.8%) and the mean age of ERT initiation was 29.0 ± 13.5 years. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%), which was less than ∼60% as previously reported for IARs. Most AEs were mild or moderate and no AE caused permanent treatment discontinuation or death. The mean plasma GL-3 and Lyso-GL-3 levels decreased remarkably at week 6 and remained stable throughout the trial, with the mean percentage reduction from baseline to week 6 through week 48 ranged from −34.6% ± 27.4% to ­41.9% ± 14.9% and −58.8% ± 20.2% to ­64.9% ± 12.7%, respectively (Fig. 1a and b). The reduction was more remarkable for the classic male patients (n = 18; GL-3: 7.99 ± 2.19 ug/mL at baseline and 4.31 ± 1.71 ug/mL at week 48, −46.0% ± 18.4%; Lyso-GL-3: 83.11 ± 25.69 ng/mL at baseline and 25.89 ± 13.43 ng/mL at week 48, −67.8% ± 17.6%). Thirteen (59.1%) participants experienced improved FD symptoms at week 48, with no cases of worsening symptoms. The mean eGFR was 115.6 ± 37.3 mL/min/1.73 m2 at baseline and 118.4 ± 42.9 mL/min/1.73 m2 at week 48, with a change of 0.0 ± 12.4 mL/min/1.73 m2 from baseline to week 48 (Fig. 1c). In the subgroup analysis, participants were divided into the younger group with age &amp;lt;30 years (n = 11) and the older group with age ≥30 years (n = 11) according to their age of ERT initiation. At week 48, the reduction of mean plasma GL-3 (−47.1% ± 23.6% vs −22.0% ± 26.0%) and Lyso-GL-3 levels (−72.4 ± 17.3% vs −48.2% ± 19.8%), the stabilization of renal function (the mean change of eGFR from baseline to week 48: 5.2 ± 7.9 mL/min/1.73 m2 vs −5.2 ± 14.1 mL/min/1.73 m2) and the percentage of symptom improvement (81.8% vs. 36.4%) were generally more remarkable in the younger group than in the older group (Table 1). Conclusion This first phase 4 study of ERT for Fabry disease in China demonstrates that agalsidase beta is safe and well tolerated with a relatively low IAR rate, and effective in reducing plasma GL-3 and Lyso-GL-3, improving symptoms, and stabilizing renal function in Chinese patients with FD. Furthermore, the present study implies that patients who initiate ERT at a younger age benefit more from the therapy. Funding: Commercial support - Sanofi Pharmaceuticals.

#496 Individualized approach in dialysate sodium prescription—safe and effective

Abstract Background and Aims The management of Na+ levels in hemodialysis (HD) patients plays a crucial role in maintaining their overall health and well-being. Na+, an essential electrolyte, is responsible for maintaining fluid balance, nerve function, and muscle contraction. However, in end-stage renal disease (ESRD) patients undergoing HD, Na+ imbalances are common and can have detrimental effects on their cardiovascular health. Furthermore, HD patients have been prescribed a standardized dialysis bath Na+ concentration (dNa+) during their HD sessions. The individualized approach aims to optimize Na+ balance, minimize adverse effects, and improve patient outcomes. Additionally, dietary Na+ intake, fluid status, and interdialytic weight gain (IDWG) also influence Na+ levels and should be considered when determining the appropriate Na+ prescription. The study aimed to assess whether an individualized dNa+ prescription can contribute to lower IDWG, expressed as a percent of prescribed dry weight (IDWG%). Method This retrospective, non-interventional study included all &amp;gt;18-year-old patients undergoing hemodialysis for &amp;gt;90 days at a single center. Patients were followed for a period of 18 months (December 2021–June 2023), during which the dNa+ concentration was gradually changed, as part of routine clinical care, until a gradient between plasma and dialysis bath Na+ of −2 mEq/L was achieved. Plasma Na+ levels were measured once monthly before a dialysis session along with other parameters such as IDWG and blood pressure. Results A total of 79 patients were enrolled in the study. The average age of the patients was 63.33 ± 12.1 years, with 43 (54.4%) being male. At baseline, the average duration of HD treatment was 255 ± 2.36 minutes, and the mean blood pump rate was 384.7 ± 42.81 ml/min. The majority of patients (98.8%) received HD treatments thrice weekly. Starting from January 2022, the mean dNa+ concentration decreased non-significantly from 139.39 ± 0.96 mmol/L to 138.99 ± 3.18 mmol/L, p = 0.13. The mean plasma Na+ concentration increased from 133.25 ± 2.9 to 136.59 ± 3.47 mmol/L, p &amp;lt; 0.00001, and while mean systolic blood pressure increased slightly (118.38 ± 12.25 to 122.87 ± 12.43, p = 0.01), it remained well controlled. The mean IDWG% decreased from 3.53 ± 1.34%, to 2.74 ± 1.35%, p = 0.35 and the proportion of patients with IDWG &amp;gt;5% decreased remarkably by more than half (11.4% to 5.1%), but due to the low patient numbers, the finding did not quite reach significance (p = 0.15, Table 1). Conclusion Our study demonstrates that individualized dNa+ management in HD patients is a beneficial approach, contributing to a decrease in the proportion of patients with severe IDWG increase, thereby addressing a crucial cardiovascular risk factor. Systolic blood pressure before dialysis remained well controlled, despite a slight, but significant increase. Our findings underscore the safety and potential benefits of an individualized approach to dialysate Na+ concentration, encouraging further exploration for enhanced HD patient care and increased overall well-being.

Effects of CYP3A5*3 genetic polymorphisms on the pharmacokinetics of perampanel in Chinese pediatric patients with epilepsy.

This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. The plasma concentration showed a linear correlation with the daily dose taken ( r = 0.17; P < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ± 297.1 vs. 633.8 ± 305.5 μg/ml; P = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ± 1.7 vs. 3.8 ± 2.0; P = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ± 293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ± 165.6 ng/ml and 260.0 ± 36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ± 285.6 vs. 433.0 ± 227.2 ng/ml; P = 0.042). The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.

Increased TMEM166 Level in Patients with Postoperative Stroke after Carotid Endarterectomy

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia–reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA.

Infliximab Tissue Concentrations in Patients With Stable Ulcerative Colitis Are Correlated With More Durable Infliximab-associated Disease Remission.

We aimed to determine the correlation between tissue and plasma infliximab concentrations in an outpatient ulcerative colitis (UC) cohort based on histologic disease activity in addition to their relationship with long-term clinical outcomes. We assessed intraparticipant variability in infliximab concentrations between adjacent intestinal samples and the correlation between disease activity and tumor necrosis factor-α (TNF-α). A prospective cohort study was conducted in participants with UC receiving infliximab. Blood and 2 sigmoid colon biopsies were obtained at the index colonoscopy for infliximab and TNF-α quantification. Histological disease activity was assessed. Participants were followed for 2 years for the occurrence of hospitalization, surgery, disease relapse, and infliximab discontinuation. A positive correlation was observed between mean plasma and uninflamed tissue infliximab concentrations only (Rs = 0.75, P = .0071). Lower mean tissue infliximab concentrations correlated with a shorter time to disease relapse vs those with higher mean tissue concentrations (Rs = 0.77, P = .032). This was not seen when using plasma infliximab concentrations. Additionally, no significant intraparticipant variability of infliximab concentrations was observed for all participants independent of disease activity. Neither plasma nor tissue TNF-α correlated with disease activity. These findings support data generated in patients with Crohn's disease: plasma infliximab concentrations are reflective of infliximab exposure in tissue in the UC patient in remission, but not for those with active disease. Increasing tissue concentrations in the noninflamed tissues may improve durability of infliximab. Neither plasma nor tissue TNF-α appear to correlate with UC disease activity. Larger follow-up studies would be of benefit.

Pharmacokinetics and Safety of Atogepant Co-administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open-Label, Drug-Drug Interaction Study.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P-gp and CYP2D6 inhibitor. A phase 1 open-label study evaluated the effect of P-gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co-administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co-administration. The overall systemic exposure, the area under the plasma concentration-time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co-administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment-emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1-2 days. Co-administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co-administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P-gp.

Abstract PO5-27-06: Development of TTX-MC138, a First-In-Class miRNA-10b-Targeted Therapeutic Against Metastatic Cancers of Diverse Primary Disease Origins

Abstract Conventional therapies targeted towards the primary tumor cell oftentimes do not affect the metastatic cell and, in fact, may promote metastasis. For these reasons, our research has focused on developing therapies specific to unique properties of metastatic tumor cells. In our earlier work, we identified miRNA-10b as a master regulator of the viability of metastatic tumor cells. We determined that miRNA-10b not only promotes the capacity of tumor cells to migrate and invade surrounding tissue, but, importantly, serves as a powerful master regulator of the viability of cancer cells. This knowledge allowed us to develop a therapeutic miR-10b inhibitor, named TTX-MC138, which is effectively delivered to metastatic tumor cells and can elicit complete responses and life-long disease remissions in preclinical models of breast and pancreatic adenocarcinoma. As a critical step towards de-risking further clinical development of TTX-MC138, we have embarked on a Phase 0 clinical trial with Cu64-labeled TTX-MC138. The trial involves microdose injection of Cu64-labeled TTX-MC138 into stage IV breast cancer patients, followed by positron emission tomography-magnetic resonance imaging (PET-MRI). The study seeks to determine the pharmacokinetics of TTX-MC138 and its uptake in metastatic lesions. The impact of this work is three-fold. First it can establish that TTX-MC138, which is so effective in mice, will also accumulate in human metastases. This greatly de-risks the clinical development of the therapeutic because it shows drug delivery is indeed feasible. Second, the Phase 0 studies will reveal the pharmacokinetic behavior of TTX-MC138 which will allow one to establish dosing during therapy. Third, once TTX-MC138 reaches late-stage clinical trials, one can use the radiolabeled therapeutic to select patients for treatment, based on which patients’ metastases accumulate the drug. Studies that we present in support of the Phase 0 trial include dosimetry/PK and tissue distribution studies, as well as metabolite analysis in non-human primates. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation) and the mean plasma blood half-life was 11.5 ± 1.8 h. RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. Combined, these studies support first-in-human testing of TTX-MC138 for the treatment of metastatic cancer and, by addressing the issue of drug delivery, enable the clinical development of a wide array of TTX-based therapeutics. Citation Format: Zdravka Medarova, Neil Robertson, Subrata Ghosh, Andreas Varkaris, Peter Caravan, Susan Duggan. Development of TTX-MC138, a First-In-Class miRNA-10b-Targeted Therapeutic Against Metastatic Cancers of Diverse Primary Disease Origins [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-27-06.

Subcutaneous administration of ceftazidime at 20 and 40 mg/kg produces theoretically therapeutic plasma concentrations for at least 120 hours in red-eared sliders (Trachemys scripta elegans).

To evaluate and compare the pharmacokinetic parameters of SC ceftazidime administered at 20 and 40 mg/kg to red-eared sliders. 8 adult red-eared sliders (Trachemys scripta elegans). In a sequential, 2-period study with a 3-week washout period between treatments, ceftazidime was administered SC to turtles at 20 and 40 mg/kg. Blood samples were collected from the subcarapacial sinus at 0, 24, 48, 72, 96, and 120 hours after ceftazidime administration. Plasma ceftazidime concentrations were quantified using reversed-phase HPLC. Mean plasma half-life after 20- and 40-mg/kg dosing was 39.75 ± 8.0 hours and 33.03 ± 6.56 hours, respectively. Mean maximum plasma concentration after 20- and 40-mg/kg dosing was 71.0 ± 15.93 µg/mL and 120.0 ± 30.62 µg/mL, respectively. Mean plasma ceftazidime concentrations remained ≥ 8 µg/mL, the theoretical MIC for various reptile pathogens for all time points. Results indicate that ceftazidime dosed at either 20 or 40 mg/kg produces plasma concentrations exceeding the theoretical MIC of various reptile pathogens for at least 120 hours. An ideal dosing interval could not be determined, as all plasma concentrations remained above the threshold of interest for all time points. Follow-up studies should focus on establishing a dosing interval and more rigorous monitoring for potential adverse effects.

Effects of d-alanine Intake on Amino Acid Metabolism and Kidney Function in Healthy Adults: A Multicenter, Randomized Pilot Study

Backgroundd-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans. ObjectiveThis study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers. MethodsThis multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters. ResultsWe randomly assigned 24 participants to the 3-g (n = 12) and 6-g d-alanine (n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m2. The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1–167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m2 in the 6-g d-alanine group (P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants. Conclusionsd-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466.

Therapeutic Drug Monitoring of Isoniazid Among Newly Diagnosed Pulmonary Tuberculosis Patients

Introduction: Tuberculosis has a higher incidence in lower income countries. Positive treatment outcomes may be fewer due to comorbidities like diabetes mellitus and immunosuppressive illnesses. The Global Tuberculosis Network working under the umbrella of World Health Organization has composed different committees. The TB Pharmacology Committee has given the concept of precision medicine and treatment based on drug susceptibility testing. Achievement of optimum plasma levels of anti-tuberculous drugs by therapeutic drug monitoring (TDM) is imperative and being emphasized to achieve a TB cure. Aims and Objectives: To determine the levels of INH in low responders to ATT have lower plasma levels of Isoniazid. Place and Duration of study: University of Health Sciences and Gulab Devi Chest Hospital, Lahore, for 1 year from August 2017- July 2018. Material and Methods: A first dose therapeutic drug monitoring (TDM) of isoniazid (INH) was planned in 25 newly enrolled sputum positive tuberculous patients at Gulab-Devi Hospital. The work was approved by Ethical Review Committee. Fixed dose combination (FDC) of anti-tuberculous drugs was given under direct observation and blood samples were withdrawn at two hours (C2h) and six hours (C6h) on days one, 14 and 56th of drug therapy. Samples of sputum for acid fast bacilli (AFB) were also taken during blood sampling. Method development and validation of isoniazid estimation by high-performance liquid chromatography was carried out. Plasma INH concentration in test samples was measured with Shimadzu Chromatographic System, Japan. Data was entered and analyzed using SPSS version 20. A p value ? 0.05 was taken as statistically significant. Results: Among 25 patients enrolled to the current study, the mean plasma levels of isoniazid were 1.29±0.79 µg / ml and 0.56±0.43 µg / ml at two hours and six hours respectively throughout the research duration. Most of the patients had lesser plasma INH levels than the target ranges (&lt; 3µg / ml). Sputum for acid fast bacilli was found 100% positive on day one and 14 however sputum conversion was 56% after four weeks drug therapy. Conclusion: An early TDM monitoring has revealed low plasma INH concentration. Correction of dose to achieve expected plasma INH level will have promising effect on sputum culture conversion. It will minimize the total statewide burden of slow responders and tuberculosis resistant cases.

Evaluation of soluble P-selectin as a predictive biomarker in acute symptomatic pulmonary embolism: Insights from a prospective observational study.

Soluble P-selectin (sP-selectin) has been proposed as a potential biomarker for venous thromboembolism (VTE) diagnosis with interesting results. However, its role in predicting early mortality in pulmonary embolism (PE) remains unexplored. This observational, prospective, single-center study enrolled consecutive patients aged 18 or older with confirmed acute symptomatic PE and no prior anticoagulation. The study aims to assess the prognostic capacity of sP-selectin measured at the time of PE diagnosis for short-term mortality and major bleeding. A total of 196 patients, with a mean age of 69.1 years (SD 17), were included, of whom 52.6% were male. Within 30 days, 9.7% of patients (n = 19) died, and 5.1% (n = 10) suffered major bleeding. PE risk stratification revealed 4.6% (n = 9) with high-risk PE, 34.7% (n = 68) with intermediate-high-risk PE, 38.3% (n = 75) with intermediate-low-risk PE, and 22.5% (n = 44) with low-risk PE according to the European Society of Cardiology score. Mean plasma sP-selectin levels were comparable between survivors and non-survivors (489.7 ng/mL ±63 vs. 497.3 ng/mL ±51; p = .9). The ROC curve for 30-day all-cause mortality and major bleeding yielded an AUC of 0.49 (95% CI 0.36-0.63) and 0.46 (95% CI 0.24-0.68), respectively. Multivariate and survival analyses were precluded due to lack of significance. sP-selectin was not useful for predicting short-term mortality or major bleeding in patients with acute symptomatic pulmonary embolism. Further studies are required to clarify the role of sP-selectin in VTE, particularly in prognosticating PE outcomes.