Serum Drug Concentrations Research Articles

P-1258. Unlocking Potentials: The Impact of Meropenem, Meropenem-vaborbactam, and Ceftazidime-avibactam in Combatting Carbapenem-Resistant Enterobacter cloacae in Epithelial Lining Fluid and Serum

Abstract Background Carbapenem-resistant Enterobacterales (CRE) are an urgent threat. We modeled epithelial lining fluid (ELF) and serum concentrations of meropenem (MER), meropenem-vaborbactam (MV), and ceftazidime-avibactam (CA) to assist in treatment selection. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating ELF concentrations with a non-CP-producing CRE Methods Two E. cloacae were evaluated, one a non-carbapenemase (CP) producing isolate with multiple porin mutations and blaACT-15, and one blaKPC-3 CP-producing isolate. One compartment IVPD models were run in duplicate for ELF and humanized serum concentration targets. Models were sampled for CFU/mL counts at 0, 4, 6, 8, 24, 32, 48, 72, 96, and 120h. Concentrations were extrapolated from population-pharmacokinetic data to reflect free drug concentrations in ELF and serum. Antibiotics were administered as a bolus, with serum models also run as an extended infusion (EI). Susceptibility changes, via E-test, were evaluated every 24h and compared to 0h. Bactericidal activity was defined as ≥3log10 CFU/mL reduction from the initial inoculum, and bacteriostatic activity as < 3 log10 CFU/mL reduction. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating serum concentrations at steady state with a CP-producing CRE Results BlaACT-15 isolate: ELF concentrations of MER and MV were bactericidal through 24h with MIC shifts in both treatments, including MER MIC shifts to >32μg/mL and MV MIC shifts to 16μg/mL. CA ELF concentrations were bacteriostatic through 48h before bacterial regrowth above the initial inoculum and MIC shifts to 64μg/mL. All bolus serum antimicrobial concentrations resulted in bactericidal activity, however, only MV remained bactericidal at 120h with no MIC shifts. EI-MER and EI-MV alternatively were bacteriostatic after 48h. BlaKPC-3 isolate: Bactericidal activity was only observed with MV, in ELF models with no MIC shift. CA and MER ELF concentrations had bacterial regrowth after 24h. MIC shifts included a change to >256μg/mL after CA exposure. Serum concentrations of CA and MV were bacteriostatic through 24h. CA and MV serum models had bacterial regrowth after 72h with MIC shifts to 16μg/mL for CA. No MIC shifts were observed with serum MV. Bolus and EI results were similar for all. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating serum concentrations at steady state with a non-CP-producing CRE Conclusion MV serum concentrations were the most active therapy, with no MIC shifts, for two CRE E. cloacae IVPD models. ELF concentrations should be considered as a contributing factor to treatment failure and resistance development. Meropenem, meropenem-vaborbactam, and ceftazidime-avibactam dosing simulating ELF concentrations with a CP-producing CRE Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Kerry L. LaPlante, Pharm.D., FCCP, FIDSA, FIDP, Abbive: Advisor/Consultant|Abbive: Grant/Research Support|Ferring: Advisor/Consultant|Gilead: Grant/Research Support|Melinta: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Grant/Research Support

Preclinical evaluation of new drug-drug interactions of lomitapide: A proposal for novel mechanism of interaction associated with lipid metabolic changes.

Lomitapide, a microsomal triglyceride transfer protein inhibitor, is a lipid-lowering drug that inhibits chylomicron formation in enterocytes and very low-density lipoprotein (VLDL) formation in the liver. Previous studies have shown that very low-density lipoprotein and/or low-density lipoprotein (VLDL/LDL) can deliver certain drugs in addition to lipids. Thus, we hypothesized that serum concentrations of drugs that are more likely to be distributed to VLDL/LDL in the serum (referred to as "VLDL/LDL-philic drugs" in this paper) may be altered by co-administered lomitapide. To verify this interest, we administered VLDL/LDL-philic drugs along with lomitapide to mice. Repeated administration of lomitapide decreased the serum lipid levels and VLDL/LDL-philic drug concentrations, to 20% for amiodarone, to 52% for doxycycline, and to 62% for tetracycline. These decreases occurred concurrently with the accumulation of lipids and drugs in enterocytes. The enterocyte distribution coefficients, defined as the amount of drug in enterocytes divided by the serum drug concentration, were significantly increased by lomitapide treatment for all the VLDL/LDL-philic drugs tested. In addition, an acute absorption study showed that amiodarone absorption was reduced to less than 30% by lomitapide, accompanied by accumulation of amiodarone in enterocytes. Collectively, through a series of experiments, we revealed the association between drugs and VLDL/LDL, and their impact on pharmacokinetics. Our study suggested that lomitapide decreases serum concentrations of VLDL/LDL-philic drugs probably due to changes in their absorption kinetics, proposing novel drug-drug interactions associated with lipid metabolic changes.

Investigating “Xinshuixiao” Serum's Impact on dDAVP-Induced AQP2 Expression and Mechanisms in IMCD3 Cells

Objective To investigate the impact of “Xinshuixiao” drug-containing serum on dDAVP-induced AQP2 expression in IMCD3 cells and to preliminarily explore its underlying mechanisms. Methods Rats were orally administered with “Xinshuixiao granules” containing medicinal compounds. The CCK-8 assay was employed to determine the appropriate drug serum concentration and its effect on IMCD3 cell viability. Additionally, we assessed the influence of “Xinshuixiao” drug-containing serum on IMCD3 cell activity following dDAVP intervention. Cells were divided into blank, model, low, medium, and high-dose “Xinshuixiao” drug serum groups, as well as a Tolvaptan group. After 24 h of drug treatment, ELISA was used to measure the levels of arginine vasopressin (AVP), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) in the cell supernatant. Western blotting was employed to evaluate AQP2 protein expression, and real-time polymerase chain reaction (Real-time PCR) was used to assess AQP2 mRNA expression levels. Results In comparison to the blank group, the model group exhibited elevated expression of AVP, cAMP, PKA ( P<0.05), as well as increased AQP2 mRNA and protein expression ( P<0.05). When compared to the model group, all treatment groups displayed varying degrees of reductions in AVP, cAMP, and PKA expression ( P<0.05), along with decreased AQP2 mRNA and protein expression, with statistically significant differences ( P<0.05). Conclusion “Xinshuixiao” drug-containing serum exerts an inhibitory effect on the overexpression of AQP2 induced by dDAVP in IMCD3 cells, which may be associated with its suppression of the cAMP/PKA signaling pathway.

Prednisolone pharmacokinetics in dogs with protein-losing enteropathy.

It is unknown if glucocorticoid malabsorption contributes to the approximate 50% treatment failure rate in dogs with protein-losing enteropathy (PLE). To compare pharmacokinetics (PK) of orally administered prednisolone in dogs with PLE vs healthy controls. Fourteen dogs with well-characterized PLE and 7 control dogs. Prospective case-controlled study. Dogs were treated with 1 mg/kg prednisolone PO once daily for approximately 3 weeks. Venous blood samples were collected at set timepoints before and after prednisolone administration on the first (T1) and final (T2) study days. Total and non-protein bound serum prednisolone concentrations were determined using liquid chromatography tandem-mass spectrometry, and pharmacokinetics variables were derived from the drug concentration data. Pharmacokinetics variables were compared between PLE and control dogs and between PLE short-term responders and non-responders. The PLE dogs had a shorter half-life of the terminal slope than control dogs (harmonic mean of 1.3 vs 1.8 hours; P = .05) whereas the percentage of serum prednisolone that was non-protein bound was higher in PLE dogs than in control dogs (median of 15.7% vs 6.7%; P = .02) at T1. Total prednisolone drug exposures and maximum total serum drug concentrations did not differ between PLE and control dogs at T1 or T2, nor did they differ between short-term responders and non-responders within the PLE population (P > .05 for all comparisons). Overall drug exposures are similar between PLE dogs and healthy controls. Glucocorticoid malabsorption is unlikely to be a common cause of treatment failure in dogs with PLE.

FC30 Precision biologic dosing in psoriasis: development, validation and beta-testing of a therapeutic drug monitoring dashboard

Abstract Following the advent of biologic therapies for chronic plaque psoriasis, achieving clear/nearly clear skin (disease control) has become a realistic goal. Patients currently continue high-cost biologic therapy indefinitely once they have achieved disease control, which leads to a long-term drug and healthcare burden. Clinical trial data indicate that some individuals can maintain disease control with less frequent doses, especially those who have higher serum drug concentrations, indicating a role for therapeutic drug monitoring (TDM) in guiding dosing decisions. To enable real-world implementation of TDM-guided precision dosing of biologics, we developed, validated, and beta-tested an online interactive TDM dashboard, powered by a pharmacokinetic (PK) model. We searched for population PK models of the exemplar psoriasis biologic risankizumab in PKPDAI and PubMed databases. We externally validated the PK model using an independent multicentre real-world UK psoriasis dataset (n = 50 patients, BSTOP study) prior to embedding it within an online R Shiny interactive dashboard. Two rounds of beta-testing of the TDM dashboard were performed with healthcare professionals to assess usability. A two-compartment PK model with first-order absorption and elimination processes was identified. The PK model was based on Phase I–III trial data and adopted a nonlinear mixed effects approach (13 123 observations from 1899 patients; 71% male; median age, 47; median weight, 97 kg; Suleiman et al., Clin Pharmacokinet 2019). We integrated the model into an online R Shiny interactive dashboard, which generates a personalized dosing interval for risankizumab. The model is used as a Bayesian prior, to predict individual patient parameters using their serum drug concentrations, dose history and other covariates (weight, serum concentrations of anti-drug antibody, albumin and creatinine). Individual predictions were externally validated (mean absolute error 0.95 mg/L; mean percentage error 17.6%; root mean square error 1.7 mg/L; R2 0.8). Beta-testing sessions with 29 clinicians (58% female; mean age 41; 33% doctor; 42% nurse) from 8 UK dermatology centres showed above-average usability of the dashboard (mean System Usability Scale score 72/100, rating ‘good’). All participants evaluated the dashboard as user-friendly and rated it acceptable or completely acceptable. Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Mean time to generate a dosing interval using the dashboard was 1.9 min (SD 1.2). Our study provides a novel pipeline for the implementation of TDM-enabled precision dosing of biologics in real-world practice. Our user-friendly online TDM dashboard has the potential to incorporate other biologic therapies and can be extended across disease contexts (including non-response and other immune-mediated inflammatory diseases) for maximal real-world health benefits and cost saving.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study.

Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration-time curve from time 0 to the last concentration-quantifiable time t (AUC0-t), maximum serum drug concentration (Cmax), and area under the serum drug concentration-time curve from time 0 to infinity (AUC0-inf). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC0-t, Cmax, and AUC0-inf between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80-1.25 (AUC0-t, 0.91-1.13; Cmax, 0.91-1.13; AUC0-inf, 0.91-1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.

Serum Concentration of Antidepressant Drugs in Geriatric Day Care Patients With Renal Insufficiency and Multimorbidity.

Geriatric depression is challenging to treat owing to age-related changes in pharmacokinetics and comorbidities. Although renal insufficiency and multimorbidity are typical geriatric complications that cannot be completely separated from each other, no study has examined the influence of these factors on the serum concentrations of antidepressants. For the first time, we evaluated the effects of these factors in combination on the dose-corrected serum concentration (C/D) of antidepressants in geriatric patients. In this retrospective study, data from 123 geriatric patients in a gerontopsychiatric day care unit at the University Hospital of Würzburg were analyzed. Multiple linear regression analysis and analysis of variance with confounders were used to examine the associations between glomerular filtration rate (GFR) and stages of renal impairment and the C/D of venlafaxine, mirtazapine, sertraline, and escitalopram corrected for multimorbidity, sex, lithium intake, and the number of triple whammy drugs. GFR (P < 0.001, ß = -0.070) was associated with the C/D of the active moiety of venlafaxine (N = 32). GFR, multimorbidity, and sex were not associated with the C/D of mirtazapine, escitalopram, or sertraline. As the influence of sex may be less pronounced than that of decreasing GFR in terms of the C/D of the active moiety of venlafaxine in geriatric patients, we recommend considering the GFR for dose adjustment rather than sex. In conclusion, even in patients with mild renal impairment, serum venlafaxine concentration should be monitored to prevent overdosing. Mirtazapine, sertraline, and escitalopram may be well-suited antidepressants for geriatric patients with renal function impairment stage 2-3 as well as multimorbidity.

Therapeutic Drug Monitoring of Antimicrobial Drugs in Children with Cancer: A New Tool for Personalized Medicine.

The risk of fungal, bacterial, and viral infections is higher in children with hematological and solid malignancies, particularly during periods of profound neutropenia. Although early administration of antimicrobial agents is common, optimizing pharmacological therapy in pediatric patients with cancer is challenging because of their variable pharmacokinetics compared with adults, including differences in body mass and augmented renal clearance, as well as chemotherapy-induced organ toxicity. Therapeutic drug monitoring, which involves measuring drug concentrations in serum or plasma at specific timepoints and adjusting doses accordingly, can be applied to various medications. While standardized targets for all antimicrobial agents in children are lacking, therapeutic drug monitoring appears to be beneficial in preventing serious toxicity and addressing treatment failure or non-compliance. This narrative review aims to analyze current perspectives on therapeutic drug monitoring for antimicrobial drugs in the special population of children with hematological or oncological diseases, including those undergoing hematopoietic cell transplantation. The review provides evidence on the clinical benefits of this method and explores potential future developments in this area.

Digoxin loading doses for atrial fibrillation in critically Ill patients

Abstract Introduction The use of digoxin, a cardiac glycoside, for inotropic effects and electrophysiologic actions date back as far as the 18th century. Loading doses (LD) of digoxin are recommended when used for rate control in the setting of atrial fibrillation or atrial flutter (AF/AFL), though the optimal serum drug concentration (SDC) remains unknown. Pharmacokinetic based formulas used to calculate a LD target a SDC of 0.8-1.2 ng/mL. Still, digoxin pharmacokinetics remain unpredictable and are influenced by age, weight, renal impairment, and critical illness. Purpose The purpose of this study was to assess the safety and efficacy of digoxin LD used in critically ill patients to rate control AF/AFL and to assess the SDC achieved after a LD. Methods We conducted an Institutional Review Board approved retrospective cohort study at New York University Langone Health between January 2013 and March 2018. Adult patients (18 years of age or older) were included if they received an intravenous digoxin LD for AF/AFL in any intensive care unit and had a digoxin SDC measured between 6 and 24 hours after the LD. Patients were excluded if they received the LD orally. The primary endpoint was the SDC achieved after the LD. Secondary safety endpoints were the incidence of supratherapeutic digoxin SDC (&amp;gt; 1.2 ng/mL). Secondary efficacy endpoints included the incidence of rate control success, defined as a heart rate (HR) less than 110 beats per minute (bpm) within 24 hours of the digoxin LD. Results A total of 92 patients were included in the final analysis. The cohort was 53% male with a median age of 72 years, median BMI of 27, a median creatinine clearance (CrCL) of 47 mL/min at the time of IV digoxin LD and 66% of the cohort had AF. The highest HR associated with the AF/AFL 24 hours prior to digoxin was 133 (121, 145) bpm. The median total LD of digoxin for the entire cohort was 11 mcg/kg (750 mcg). In those with impaired renal function (CrCl &amp;lt; 30 mL/min), the median LD of digoxin was 8.3 mcg/kg. For 61% of the cohort, the LD was distributed over 6-hour intervals. The median SDC after completion of the IV digoxin LD was 1.3 ng/mL (0.9, 1.7), with a range of 0.4-4.1 ng/mL. A SDC &amp;gt; 1.2 ng/mL was observed in 51% of the cohort. Secondary outcomes of rate control success occurred in 60% of the cohort. No patients experienced any digoxin associated dysrhythmias or required reversal. Conclusion We found a SDC of 1.3 ng/mL post a digoxin LD in critically ill patients with AF/AFL to be successful in achieving rate control in 60% of our cohort. Despite 51% of the cohort achieving a SDC &amp;gt; 1.2 ng/mL, digoxin related adverse events were uncommon. Our analysis support previous data suggesting dose adjustment of digoxin in patients with impaired renal function but suggest a higher SDC may be acceptable in the acute setting when used for rate control. Our sample size is limited, and future studies should confirm our findings in critically ill patients.

Review article: Optimisation of biologic (monoclonal antibody) therapeutic response in inflammatory bowel disease.

There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). An extensive review of the published literature. TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial. In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control.

HLA-DQA1*05 Associates With Anti-Tumor Necrosis Factor Immunogenicity and Low Adalimumab Trough Concentrations in Inflammatory Bowel Disease Patients From the SERENE Ulcerative Colitis and Crohn's Disease Studies.

Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients. We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations. This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05). We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity. SERENE CD (NCT02065570), SERENE UC (NCT02065622).

Effects of adding antibiotics to an inactivated oil-adjuvant avian influenza vaccine on vaccine characteristics and chick health

During poultry immunization, antibiotics are typically added to inactivated oil-adjuvant avian influenza (AI) vaccines. Here, we evaluated the effects of adding ceftiofur, a third-generation cephalosporin, to an AI vaccine on vaccine stability and structure and on chick growth, immune efficacy, blood concentrations, biochemical and immunological indices, and gut microbiota. The results demonstrated that neither aqueous ceftiofur sodium nor ceftiofur hydrochloride oil emulsion formed a stable mixture with the vaccine. Adding ceftiofur formulations, particularly ceftiofur hydrochloride, at >4% significantly destabilized the vaccine's water-in-oil structures. Adding ceftiofur also increased vaccine malabsorption at the injection site; specifically, adding ceftiofur hydrochloride reduced H5N8 and H7N9 antibody titers after the first immunization (P < 0.05) and H7N9 antibody titers after the second immunization (P < 0.01). Serum drug concentrations did not differ significantly between the groups with ceftiofur sodium and hydrochloride addition. Ceftiofur addition increased postvaccination chick weight loss; compared with the vaccine alone, ceftiofur sodium-vaccine mixture increased chick weight significantly (P < 0.05). Ceftiofur addition also increased stress indices and reduced antioxidant capacity significantly (P < 0.05 or P < 0.01). Vaccination-related immune stress reduced gut microbiota diversity in chicks; ceftiofur addition reversed this change. AI vaccine immunization significantly reduced the relative abundance of Lactobacillus and Muribaculaceae but significantly increased that of Bacteroides and Eubacterium coprostanoligenes group. Ceftiofur addition restored the gut microbiota structure; in particular, ceftiofur hydrochloride addition significantly increased the abundance of the harmful gut microbes Escherichia-Shigella and Enterococcus, whereas ceftiofur sodium addition significantly reduced it. The changes in gut microbiota led to alterations in metabolic pathways related to membrane transport, amino acids, and carbohydrates. In conclusion, adding ceftiofur to the AI vaccine had positive effects on chick growth and gut microbiota modulation; however, different antibiotic concentrations and formulations may disrupt vaccine structure, possibly affecting vaccine safety and immunization efficacy. Thus, the addition of antibiotics to oil-adjuvant vaccines is associated with a risk of immunization failure and should be applied to poultry with caution.

Usefulness of measuring the serum concentration of antihypertensive drugs in uncontrolled hypertension

Usefulness of measuring the serum concentration of antihypertensive drugs in uncontrolled hypertension

Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

TRLS-03. A PHASE 1/2 STUDY ASSESSING SAFETY AND PHARMACOKINETICS OF CEMIPLIMAB IN PEDIATRIC PATIENTS WITH RELAPSED OR REFRACTORY SOLID OR CENTRAL-NERVOUS-SYSTEM TUMORS AND SAFETY AND EFFICACY OF CEMIPLIMAB IN COMBINATION WITH RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA, NEWLY DIAGNOSED HIGH-GRADE GLIOMA, OR RECURRENT HIGH-GRADE GLIOMA

Abstract BACKGROUND We investigated, for the first time, combination PD-1 inhibition (cemiplimab) and radiation therapy (RT) followed by cemiplimab monotherapy in children with solid tumors, diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). METHODS We conducted a multicenter study through the Pediatric Neuro-Oncology Consortium. Phase 1 established the safety/pharmacokinetics of cemiplimab monotherapy in children (&amp;lt;18 years) with recurrent solid and central-nervous-system (CNS) tumors. Phase 2 evaluated cemiplimab/RT in children and young adults (3-25 years) with newly diagnosed (nd) DIPG, ndHGG or recurrent HGG (rHGG). Patients with ndDIPG and ndHGG were randomized to hypofractionated RT (hfRT) or conventionally fractionated RT (cRT). Primary endpoints included overall survival at 12 months (OS12) for ndDIPG and rHGG and progression-free survival at 12 months (PFS12) for ndHGG. Correlates included quality-of-life, circulating tumor DNA (ctDNA), immunogenicity, and PD-1 pathway components. RESULTS 25 patients (solid tumors, n=8; CNS tumors, n=17) were treated in phase 1; serum drug concentrations were comparable to adults. 32 patients were treated in phase 2. OS12 was 33.3% for ndDIPG treated with cemiplimab/hfRT (n=6), 0.0% for ndDIPG with cemiplimab/cRT (n=5), and 31.3% for rHGG (n=9). PFS12 was not estimable for ndHGG treated with cemiplimab/hfRT (n=5) and 20.0% for ndHGG treated with cemiplimab/cRT (n=7). 20 patients (35.1%) had grade 3/4 treatment-related AEs (TRAEs) and 13 (22.8%) had serious TRAEs. The most frequent grade 3/4 TRAE was decreased lymphocyte count (n=4 [7.0%]). 12 patients (21.1%) demonstrated treatment-emergent pseudo-progression, 2 (3.5%) grade 3/4. The most frequent serious TRAE was pseudo-progression (n=3 [5.3%]). CONCLUSIONS Cemiplimab/RT did not demonstrate an improvement in OS (ndDIPG and rHGG) or PFS (ndHGG), leading to early stopping for futility. However, the combination was tolerable, demonstrated similar outcomes across RT schedules, and showed similar exposure in serum compared to adults. Biologic and clinical correlate analyses are underway.

Therapeutic Drug Monitoring Characteristics in a City Hospital for a Year.

Therapeutic drug monitoring (TDM) involves the measurement of drug concentrations in serum, plasma, whole blood, or other biologic fluids. This study focused on evaluating the TDM requests of a city hospital over a period of one year, retrospectively. The study retrospectively analyzed TDM requests for carbamazepine, cyclosporine-A, digoxin (DIGOX), lithium (LITH), methotrexate (MTX), phenitoin, tacrolimus, and valproic acid (VALP) from June 1, 2022, to June 1, 2023. Parameters such as the age and the gender of patients, the requesting departments, the measurement results, and the turnaround time (TAT) were assessed. Drug concentrations below the reference values were classified as subtherapeutic, whereas concentrations above the reference values were considered supratherapeutic. In total, 10,913 drug concentration measurement records were analyzed. The gender distribution was 51.6% male and 48.4% female. Pediatric samples comprised 6.2% and elderly samples 8.6% of the total. Notably, DIGOX, LITH, and VALP levels showed a significant correlation with age (p = < 0.0001, p = < 0.0001, and p = 0.0002, respectively). TAT was maintained at 360 minutes (6 hours) for all tests. The study found significant correlations between age and DIGOX, LITH, and VALP levels. TDM plays a critical role in the elderly population, necessitating careful management of these drugs.

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.

e15132 Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.

A phase I dose escalation trial of BCD-145 in patients with unresectable or metastatic melanoma.

9526 Background: BCD-145 (nurulimab) is a fully human IgG1 mAb with modified Fc-fragment (the 1st Gln is replaced by Glu in the heavy chain sequence, and there is no terminal dipeptide composed by Gly and Lys residues) that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction between CTLA-4 and its ligands. This allows to stimulate T-cell proliferation, cytokine production and induces antitumor immune response. Here we present the results of multicenter open-label single-arm multi-cohort phase I trial of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity of BCD-145 in pts with unresectable/metastatic melanoma (unr/mM). Methods: BCD-145 monotherapy in 3+3 dose escalation [0.1, 0.3, 1, 3, 10 mg/kg intravenously Q3W] was given to 15 pts with unr/mM with measurable disease, who had failed prior therapy, ECOG 0-2. Pts with brain mts, previous therapy with aCTLA-4 and/or aPD-1/PD-L1 drugs were not allowed. The main objective of the study was to evaluate PK, PD, tolerability, immunogenicity, safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) identification. Secondary objectives included tumor response rate (irRECIST). Results: BCD-145 proved safety and overall was well tolerated. DLT and MTD were not reached. Any grade (Gr) adverse events (AEs) occurred in 100% (15/15) of pts. 33.3% (5/15) of pts had AE/SAE of Gr 3-4, including hypertension Gr 3 (1 at 1 mg/kg), hypercalcemia Gr 4 (2 at 1 mg/kg), hypokalemia Gr 3 (2 at 1 mg/kg), neutropenia Gr 3 (1 at 0.3 mg/kg), anemia Gr 3 (1 at 1 mg/kg), lung infection Gr 3 with hospitalization (1 at 1 mg/kg). Only 2 pts had a treatment-related AE Gr 3-4. Immuno-related AE were identified in 46.7% (7/15), manifested by symptoms of thyroiditis (mainly Gr 1) and diarrhea Gr 2 (1 at 10 mg/kg). There was 1 death (at 1 mg/kg) due to progression. There is dose-dependent peak study drug serum concentrations and systemic exposure. Two dosage regimens (1 mg/kg, 3 mg/kg Q3W) allowed to achieve the optimal concentration. BCD-145 increased subpopulations of activated HLA-DR+ CD4+ and CD8+ T lymphocytes, CD4+ICOS+ T-lymphocytes, absolute lymphocyte counts in all cohorts without significant differences. Binding and neutralizing Abs against BCD-145 were detected in 2 pts from different dose cohorts (0.3 mg/kg, 1 mg/kg). PR and SD were registered in 2 pts of each response group. 30.8% of pts achieved disease control, which is consistent with published data on other CTLA-4 inhibitors. A dose of 1 mg/kg is determined as recommended phase 2 dose (RP2D). Conclusions: BCD-145 demonstrated a tolerable safety profile and preliminary anti-tumor activity in pts with unr/mM. Anti-tumor effects of BCD-145 were observed in pts who had progressed on prior treatment. Further co-targeting PD-1 and CTLA-4 simultaneously will achieve a better anti-tumor activity due to cooperative binding to exhausted T-cell subsets. Clinical trial information: NCT03472027 .

Effects of vatinoxan in rats sedated with a combination of medetomidine, midazolam and fentanyl

BackgroundAlpha2-adrenoceptor agonists (α2-agonists) are widely used in animals as sedatives and for pre-anaesthetic medication. Medetomidine has often been given subcutaneously (SC) to rats, although its absorption rate is slow and the individual variation in serum drug concentrations is high via this route. In addition, α2-agonists have various effects on metabolic and endocrine functions such as hypoinsulinaemia, hyperglycaemia and diuresis. Vatinoxan is a peripherally acting α2-adrenoceptor antagonist that, as a hydrophilic molecule, does not cross the blood-brain barrier in significant quantities and thus alleviates peripheral cardiovascular effects and adverse metabolic effects of α2-agonists. Aim of this study was to evaluate the effects of vatinoxan on sedation, blood glucose concentration, voiding and heart and respiratory rates and arterial oxygen saturation in rats sedated with subcutaneous medetomidine, midazolam and fentanyl.ResultsOnset of sedation and loss of righting reflex occurred significantly faster with vatinoxan [5.35 ± 1.08 (mean ± SD) versus 12.97 ± 6.18 min and 6.53 ± 2.18 versus 14.47 ± 7.28 min, respectively]. No significant differences were detected in heart and respiratory rates and arterial oxygen saturation between treatments. Blood glucose concentration (18.3 ± 3.6 versus 11.8 ± 1.2 mmol/L) and spontaneous urinary voiding [35.9 (15.1–41.6), range (median) versus 0.9 (0–8.0) mL /kg/min] were significantly higher without vatinoxan.ConclusionsAcceleration of induction of sedation, alleviation of hyperglycaemia and prevention of profuse diuresis by vatinoxan may be beneficial when sedating rats for clinical and experimental purposes with subcutaneous medetomidine, midazolam and fentanyl.

Анти-Ха активность у пациентов с неклапанной фибрилляцией предсердий на фоне приема апиксабана и ривароксабана

Direct oral anticoagulants (DOAC) are widely used for prevention of stroke in patients with atrial fibrillation. The need for therapeutic drug monitoring of DOACs remains unclear. Measurement of anti-Xa activity that directly correlates with serum drug concentration seems to be a promising approach for monitoring of Xa inhibitors.