Standard Dosing Regimen Research Articles

Pharmacokinetic and pharmacodynamic properties of polymyxin B in Escherichia coli and Klebsiella pneumoniae murine infection models.

Although polymyxin B has been in use since the late 1950s, there have been limited studies done to unravel its pharmacokinetics (PK) and pharmacodynamics (PD) index. We determined, in neutropenic infected mice, the PK, plasma protein binding and PK/PD index best correlating with efficacy for Escherichia coli and Klebsiella pneumoniae strains. The pharmacokinetic profile showed non-linear PK; dose was significantly correlated with absorption rate and clearance. The inhibitory sigmoid dose-effect model for the fCmax/MIC index of E. coli fitted best, but was only modestly higher than the R2 of %fT>MIC and fAUC/MIC (R2 0.91-0.93). For K. pneumoniae the fAUC/MIC index had the best fit, which was slightly higher than the R2 of %fT>MIC and fCmax/MIC (R2 0.85-0.91). Static targets of polymyxin B fAUC/MIC were 27.5-102.6 (median 63.5) and 5.9-60.5 (median 11.6) in E. coli and in K. pneumoniae isolates, respectively. A 1 log kill effect was only reached in two E. coli isolates and one K. pneumoniae. The PTA with the standard dosing was low for isolates with MIC >0.25 mg/L. This study confirms that fAUC/MIC can describe the exposure-response relationship for polymyxin B. The 1 log kill effect was achieved in the minority of the isolates whereas polymyxin B PK/PD targets cannot be attained for the majority of clinical isolates with the standard dosing regimen, indicating that polymyxin B may be not effective against serious infections as monotherapy.

P389 Switching infliximab to subcutaneous from intravenous therapy (SWIMSUIT) – A prospective, real-world, single centre, phase IV interventional study.

Abstract Background Subcutaneous (SC) infliximab (CT-P13) was approved in 2020 by the EMA for use in IBD. This offers patients greater choice, flexibility and the convenience of administering their treatment at home as well as other potential therapeutic benefits. We aim to evaluate the clinical outcomes of patients switching from intravenous (IV) infliximab to SC CT-P13. Methods We offered IBD patients established on IV infliximab (>4 doses) the opportunity to switch to SC CT-P13. Patients who agreed to switch were followed up every 12 weeks for 24 weeks. Demographics, disease history, disease activity scores, IBD CONTROL PROM, SF36, calprotectin, standard blood tests, infliximab drug levels, antidrug antibodies (ADA) and adverse events were collected at each visit. The primary endpoint was the maintenance of clinical status at week 24 (W24). A failure to maintain clinical status was defined as an increase in disease activity scores (mHBI or SCCAI) of ≥3, and/or a decline in IBD-Control PROM score of ≥4 points at any time during the study period. Results We approached 204 patients receiving IV infliximab, of which 120 patients switched to SC CT-P13 (75.8% CD, 22.5% UC, 1.7% IBDU). 24 patients had perianal disease at baseline. Median age was 38. The median time taken by patients (leaving home to returning home) to receive their infusions was 180 minutes (range 60 to 660). 96 participants were on concomitant immunomodulators (79 thiopurines, 17 methotrexate) and 105 were treated with SB2 preswitch. The median duration of IV infliximab prior to switching was 45 months. 70 (58%) of the patients were on the standard dosing (5mg/kg Q8W) regimen. All patients were switched to 120mg of SC CT-P13 every other week, regardless of their baseline regimen. 11 (9.2%) patients discontinued the treatment prior to finishing the study. 75% (CI 0.65, 0.82) of the whole cohort reached the primary endpoint of maintaining clinical status at week 24. There was no statistically significant difference in disease activity scores or IBD-Control PROM between baseline and W24. 31 (25.8%) of the patients had evidence of immunogenicity at baseline (ADA of > 50ng/ml). Of the 89 patients with no immunogenicity at baseline, 69 (77.5%) maintained this at W24. The median serum infliximab levels increased by 72.8 % from baseline to W24 (3.05 µg/ml to 5.27 µg/ml (figure 1)). Median ADA levels increased from 8.46 ng/ml at baseline to 10.6 ng/ml at W24 (figure 2). Patient satisfaction with SC CT-P13 was very high (figure 3). Conclusion Switching patients from IV to SC CT-P13 is safe, effective, and well-accepted with higher infliximab serum levels. The majority of the patients with no immunogenicity at baseline maintained this at W24.

P637 Targeting mucosal healing: dose optimization of Vedolizumab in IBD patients with inadequate endoscopic response to standard dosing

Abstract Background The GEMINI trial assessed improved clinical outcomes after an increase to 4-weekly dosing of Vedolizumab in nearly 40% of patients with insufficient response to standard 8-weekly dosing. However, later real-world data have partially questioned the efficacy of dose optimization due to the early randomization in the study design. The investigation on dose escalation efficacy of Vedolizumab in inflammatory bowel diseases (IBD) remains scarce. We aimed to explore the clinical benefit of Vedolizumab dose escalation every 4 weeks in a cohort of IBD patients with insufficient endoscopic response to the standard dosing regimen. Methods This is a retrospective single-center study. IBD patients, who showed persistent endoscopic activity (Mayo score ≥ 2 or SES-CD ≥7) with 8-weekly dosing Vedolizumab were included. Clinical data were retrieved from patients’ charts. Response after therapy optimization was compared to standard 8-weekley dosing through Wilcoxon signed-rank test for quantitative variables with non-normal distribution; univariate analysis of different factors impacting on therapy response was performed. Results A total of 52 IBD patients, 30 (57.7%) and 22 (42.3%) with ulcerative colitis and Crohn’s disease, respectively, were included. Overall, the median disease’s duration at Vedolizumab start was 12.5 month (range 3 36); 31 patients (59.6%) had been previously treated with anti-TNFs. Before Vedolizumab dose escalation 32/52 patients (61.5%) and 20/52 patients (38.5%) showed moderate (Mayo score =2; SES-CD= 7-15) and severe endoscopic activity (Mayo score =3; SES-CD ≥ 15), respectively. We observed a significant reduction of fecal calprotectin from baseline [median 133 μg/g (range 21-3800)] after Vedolizumab optimization [median 77 μg/g (range 6.0-521)] (p<0.001). After Vedolizumab optimization 28/52 patients (53.8%) obtained further endoscopic response (78.6%) or remission (21.4%) (p<0.001). At univariate analysis non exposure to anti-TNF and a lower disease duration at Vedolizumab start significantly correlated with endoscopic response after optimization (HR 0.28, 95%CI 0.32 – 0.76, and HR 0.32, 95%CI 0.25 – 0.66, respectively, p<0.001). No adverse events were observed after dose optimization in our cohort. Conclusion An increase in Vedolizumab dosing frequency is a viable treatment approach for a subset of patients with insufficient endoscopic response standard 8-weekly dosing. Higher response rates might be assessed in anti-TNF naïve patients and with a lower disease duration at therapy start. Prospective studies are needed to confirm these data.

Pharmacokinetics and Target Attainment of ß-lactam Antibiotics in Older People: A Systematic Review of Current Literature

(Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population. A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations. Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3% on cephalosporins + cephamycins, 25.3% on penicillins, 15.4% on carbapenems, and 3.3% on monobactams; 65.9% of articles involved intravenous administration, 16.5% mixed administration routes, 12.1% oral administration, and 5.5% intramuscular administration. The majority of studies had a small sample size, often did not include detailed information on the study population and methods, and were fairly old. CL was, on average, decreased, while elimination half-life was prolonged in aged subjects compared with young subjects. Volume of distribution was generally similar between age groups. Most studies identified renal function as the most important contributor to altered drug CL. In only 30.8% of the articles, target attainment was studied, and in 35.7% of these articles, target attainment was found to be suboptimal. Dosing recommendations were incorporated in 87.9% of articles. Studies frequently fail to provide an evidence-based dosing recommendation for this diverse patient population. Model-based PK studies that address both physiological and disease-related changes are urgently needed. This review identified gaps of knowledge to set priorities for further research.

Copper Super-Dosing Improves Performance of Heat-Stressed Broiler Chickens through Modulation of Expression of Proinflammatory Cytokine Genes.

Continuous exposure to high ambient temperatures brings about a number of oxidative damages in chickens. Copper (Cu), an active component of a number of antioxidative defence components, should arrest these changes to take place although that may not be possible under the standard dosing regimen followed by the industry. To ascertain the optimum dose response that may be beneficial in sustaining the performance of chickens under heat stress (HS), broiler chickens (n = 400) were exposed to high ambient temperature (between 27.2°C and 35.3°C) during 1-35 d. Copper (Cu) as Cu proteinate (Cu-P) at concentrations of 37.5, 75, 112.5, and 150 mg/kg was supplemented to the diet. The negative control (NC) diet did not contain any supplemental Cu. Increasing dietary Cu improved (P < 0.001) body weight, feed intake, and conversion ratio. Serum concentrations of total cholesterol at 21 d (P = 0.009), HDL cholesterol at 35 d (P = 0.008), LDL cholesterol at 21 d (P = 0.015), and triacylglycerol at both 21 d (P = 0.033) and 35 d (P = 0.001) decreased as Cu in the diet increased. As Cu in the diet increased, hemoglobin increased (P = 0.003) at 21 d, and the heterophil to lymphocyte ratio decreased both at 21 d (P = 0.047) and 35 d (P = 0.001). Superoxide dismutase and glutathione peroxidase activities increased when dietary Cu increased to 150 mg/kg (P < 0.01). Liver Cu at 35 d increased linearly with the dose of Cu in the diet (P = 0.0001). Selected bacteria were enumerated in the digesta to ascertain if Cu super-dosing affected their population in any way in the absence of any enteric challenge. Escherichia coli and total Salmonella numbers decreased (P = 0.0001), and total Lactobacillus increased (P = 0.0001) proportionately with dietary Cu. Interleukin-6 and tumour necrosis factor-α gene expression increased linearly (P = 0.0001) as Cu in the diet increased though the response plateaued at 112.5 mg/kg. It was concluded from the present experiment that during conditions of impending HS, dietary supplementation of 112.5 to 150 mg Cu/kg diet as Cu-P may be a novel strategy to alleviate the negative effects of HS without involving any apparent risk of Cu toxicity.

Tumor targeted delivery of mycobacterial adjuvant encapsulated chitosan nanoparticles showed potential anti-cancer activity and immune cell activation in tumor microenvironment.

Targeting immunotherapeutics inside the tumor microenvironment (TME) with intact biological activity remains a pressing issue. Mycobacterium indicus pranii (MIP), an approved adjuvant therapy for leprosy has exhibited promising results in clinical trials of lung (NSCLC) and bladder cancer. Whole MIP as well as its cell wall fraction have shown tumor growth suppression and enhanced survival in mice model of melanoma, when administered peritumorally. Clinically, peritumoral delivery remains a procedural limitation. In this study, a tumor targeted delivery system was designed, where chitosan nanoparticles loaded with MIP adjuvants, when administered intravenously showed preferential accumulation within the TME, exploiting the principle of enhanced permeability and retention effect. Bio-distribution studies revealed their highest concentration inside the tumor after 6h of administration. Interestingly, MIP adjuvant nano-formulations significantly reduced the tumor volume in the treated groups and increased the frequency of activated immune cells inside the TME. For chemoimmunotherapeutics studies, MIP nano-formulation was combined with standard dosage regimen of Paclitaxel. Combined therapy exhibited a further reduction in tumor volume relative to either of the MIP nano formulations. From this study a three-pronged strategy emerged as the underlying mechanism; chitosan and Paclitaxel have shown direct role in tumor cell death and the MIP nano-formulation activates the tumor residing immune cells which ultimately leads to the reduced tumor growth.

Meropenem for the Pharmacological Treatment of Severe Infections in Critically Ill Pediatric Patients: Breakthrough Standard Treatment Strategies Based on PK/PD.

Meropenem, as a carbapenem antibiotic, is commonly used in critically ill pediatric patients with severe infection because of its broad antimicrobial spectrum, high penetration into tissues, and favorable safety profile. Due to pathophysiological changes in critically ill children, the available evidence has demonstrated that the standard dosage regimens of meropenem could not meet an appropriate pharmacodynamic (PD) target attainment in severely infected children. Therefore, we reviewed the pharmacokinetic (PK) profile of meropenem in critically ill children, therapeutic drug monitoring (TDM), and dose optimization based on PK/PD. Meropenem kills bacteria in a time-dependent manner and its efficacy is positively correlated with the percentage of the time of dosing interval during which the free serum concentration of meropenem remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT＞MIC), which is related to PK/PD targets. For critically ill children, TDM-based dosage optimization and setting even higher PK/PD targets seem necessary to be considered. The currently available studies have revealed that increasing the dose and the application of the extended or continuous infusion of meropenem were able to achieve better PK/PD targets. According to limited clinical data on efficacy and safety, these treatment measures cannot yet be adopted as routine regimens only when serious infections caused by drug-resistant bacteria or strains with high values of MIC are suspected. Further high-quality randomized controlled trials (RCTs) or observational studies with sufficient sample sizes are required to confirm the efficacy and safety of these modes of administration.

Analyzing the Effects of Low-Dose Isotretinoin on Acne Vulgaris Against the Standard Treatment Protocol

Objective: The study's objective was to evaluate the effectiveness and safety of low-dose isotretinoin vs the standard-dose regimen for the treatment of acne vulgaris. Study Design: Randomized controlled trial Place and Duration: This study was conducted at Department of Dermatology, Bannu Medical College and Federal Government Polyclinic Hospital Islamabad in the period from March, 2022 to August, 2022. Methods: Randomization was used to split the total of 190 patients with acne vulgaris who participated in the study into two groups of 95 sample size each. Patients of both sexes were affected with acne vulgaris. Isotretinoin was administered orally to patients in group I at a dose of 20 milligrammes per day for 12 weeks, whereas patients in group II received conventional dosing regimen 80 milligrammes per day. After a total of 12 weeks of therapy, both groups had a final assessment of their effectiveness. SPSS 23.0 was used to analyze all data. Results: In all 190 cases, majority of the cases 110 (57.9%) were females and 80 (42.1%) were male patients. Mena age of the patients in group I was 24.16±10.52 years and in group II mean age was 25.8±9.87 years. We found that efficacy of conventional dosing regimen was higher in 73 (76.8%) as compared to low doze isotretinoin in 50 (52.6%) with p value &lt;0.005. Post-treatment frequency of complication were higher in group II 46 (48.4%) as compared to group I 28 (29.5%). Dry eyes and headache were the common complications in all cases. Conclusion: As a result of this research, we came to the conclusion that the typical dosing regimen for the treatment of acne vulgaris is more effective but poses a greater risk of side effects than the low dose of isotretinoin. Keywords: Efficacy, Safety, Acne vulgaris, low dose isotretinoin

597. Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis

Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT &amp;gt; MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups (Figure 1, Figure 2). Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT &amp;gt; MIC (Table 1). In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Table 1:Breakpoints (mg/L, highest minimum inhibitory concentration (MIC) with ≥ 90% PK target attainment) for different infusion durations, based on Monte Carlo simulations.Figure 1:Comparison of PTA between the two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 65% fT&amp;gt; MIC.Figure 2:Comparison of PTA between two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 100% fT&amp;gt; MIC. Conclusion To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring. Disclosures C. Buddy Creech, MD, MPH, Altimmune: Advisor/Consultant|Astellas: Advisor/Consultant|Merck: Grant/Research Support|Premier: Advisor/Consultant.

Approaches for optimizing venous thromboembolism prevention in injured patients: Findings from the consensus conference to implement optimal venous thromboembolism prophylaxis in trauma.

Venous thromboembolism (VTE) is a major issue in trauma patients. Without prophylaxis, the rate of deep venous thrombosis approaches 60% and even with chemoprophylaxis may be nearly 30%. Advances in VTE reduction are imperative to reduce the burden of this issue in the trauma population. Novel approaches in VTE prevention may include new medications, dosing regimens, and extending prophylaxis to the postdischarge phase of care. Standard dosing regimens of low-molecular-weight heparin are insufficient in trauma, shifting our focus toward alternative dosing strategies to improve prophylaxis. Mixed data suggest that anti-Xa-guided dosage, weight-based dosing, and thromboelastography are among these potential strategies. The concern for VTE in trauma does not end upon discharge, however. The risk for VTE in this population extends well beyond hospitalization. Variable extended thromboprophylaxis regimens using aspirin, low-molecular-weight heparin, and direct oral anticoagulants have been suggested to mitigate this prolonged VTE risk, but the ideal approach for outpatient VTE prevention is still unclear. As part of the 2022 Consensus Conference to Implement Optimal Venous Thromboembolism Prophylaxis in Trauma, a multidisciplinary array of participants, including physicians from multiple specialties, pharmacists, nurses, advanced practice providers, and patients met to attack these issues. This paper aims to review the current literature on novel approaches for optimizing VTE prevention in injured patients and identify research gaps that should be investigated to improve VTE rates in trauma.

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients

The proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations. Unbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT≥1MIC, 50%fT≥2MIC). There were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT≥2MIC and 95 (95%) patients met the target of 50%fT≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0-8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8-28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations. Standard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.

Linezolid Population Pharmacokinetics to Improve Dosing in Cardiosurgical Patients: Factoring a New Drug-Drug Interaction Pathway.

Linezolid-induced myelosuppression limits optimal therapy in cardiosurgical patients with deep-seated infections at current doses. Adult patients who received a cardiac surgery intervention and linezolid for a documented or presumed serious gram-positive infection were evaluated. Therapeutic monitoring data, dosing, concomitant medications, and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic model was constructed to identify covariates and test potential drug-drug interactions that may account for interpatient variability. Simulations from the final model identified doses that achieve a target therapeutic trough concentration of 2-8 mg/L. This study included 150 patients (79.3% male) with sepsis and hospital-acquired pneumonia in 71.7% as the primary indication. The population had a median (minimum-maximum) age, body weight, and estimated glomerular filtration rate (eGFR) of 66 (30-85) years, 76 (45-130) kg, and 46.8 (4.9-153.7) mL/minute, respectively. The standard linezolid dosage regimen achieved the therapeutic range in only 54.7% of patients. Lower-than-standard doses were necessary in the majority of patients (77%). A 2-compartment Michaelis-Menten clearance model with weight, kidney function, and the number of interacting drugs identified as covariates that best fit the concentration-time data was used. Cyclosporine had the greatest effect on lowering the maximum elimination rate (Vmax) of linezolid. Empiric linezolid doses of 300-450 mg every 12 hours based on eGFR and the number of interacting medications are suggested by this analysis. Lower empiric linezolid doses in cardiosurgical patients may avoid toxicities. Confirmatory studies are necessary to verify these potential drug interactions.

Population pharmacokinetics and dosing optimization of unbound teicoplanin in Chinese adult patients.

Objectives: To develop a population pharmacokinetic (PopPK) model describing unbound teicoplanin concentrations in Chinese adult patients and perform Monte Carlo simulations to optimize the dosing regimens. Methods: The raw data for PopPK analysis in this study were collected from Chinese adult patients. A PopPK model of unbound teicoplanin was developed and Monte Carlo simulations were used to optimize the dosing regimens. The trough concentrations of unbound teicoplanin were targeted at 0.75mg/L and 1.13mg/L for most infection induced by Gram-positive bacteria and endocarditis or severe infections, respectively. Results: A total of 103 teicoplanin unbound concentrations were collected from 72 Chinese adult patients. A one-compartment pharmacokinetic model with first-order elimination was established. The typical values of clearance and the volume of distribution were 11.7L/h and 811L, respectively. The clearance and volume of distribution of unbound teicoplanin were positively correlated with estimated glomerular filtration rate (eGFR) and serum albumin concentrations, respectively. Dosing simulation results showed that standard dosing regimens were unable to meet the treatment needs of all patients, and the dosing regimen need optimize based on eGFR and serum albumin concentrations. The high eGFR and serum albumin concentration were associated with reduced probability of achieving target unbound trough concentrations. Conclusion: We successfully characterized the pharmacokinetics of unbound teicoplanin in Chinese adult patients. Importantly, we further highlight the importance of guiding dosing through unbound drugs. To achieve safe and effective treatment, the dosing regimens need to be adjusted according to eGFR and serum albumin concentrations.

ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS. Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS). Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 - 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34). In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%). Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934). Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day cycle in the ongoing Phase 2 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Experience of Asciminib: Factors Associated with Response

Background - Asciminib is an allosteric BCR::ABL1 inhibitor with proven efficacy in multiply treated CML. Prior to licensing, the drug was available in the UK through a Novartis supported managed access program since 2017. Here we report our national real-world experience of asciminib, with a focus on identifying factors associated with response. Patient cohort - Fifty-three patients from 14 centres were included. The median age was 57 [23-88] years, and 29 (55%) were male. The median time from diagnosis to asciminib treatment was 69 [11-386] months, and the median number of prior tyrosine kinase inhibitors was 4 [2-5], with 33 (62%) of patients having received ponatinib. The reason for stopping the last TKI was intolerance in 33 (62%) and resistance in 20 (38%) patients. Baseline BCR:ABL1 PCRs were greater than 10% in 21 (40%) patients, 1-10% in 13 (25%), 0.1-0.999% in 8 (15%), less than 0.1% in 9 (17%) and unknown in 2 (4%). A history of tyrosine kinase domain mutations (TKDM) was present in 22 (42%) patients. T315I was most common (n=13, 25%) but non-T315I mutations were seen either alone (n=9, 17%) or in combination with a T315I mutation (n=2, 4%). Medical comorbidities were common in the group, with 30 (57%) patients having at least one cardiovascular or vascular disorder (hypertension n=18 (34%), peripheral vascular disease n=10 (19%), ischaemic heart disease n=8 (15%), atrial fibrillation n=6 (11%), stroke or transient ischaemic attack n=4 (8%)). Nine (17%) patients had chronic kidney disease and 4 (8%) had diabetes. Results - Thirty-four patients (64%) continued on treatment at the time of reporting, while 9 (17%) had stopped for resistance and 7 (13%) for intolerance. One patient had stopped for a treatment free remission attempt, one for pregnancy and one for poor compliance. The median treatment durations were 14.4 [3-51] months for those still on treatment, and 5 [1-24] and 2 [1-26] months for those stopping for resistance and intolerance, respectively. Cytogenetic response (CCyR; BCR::ABL1 PCR <1% IS) or better was achieved in 32 (58%) patients, and 29 (52%) achieved major molecular response (MMR; BCR::ABL1 PCR <0.1% IS) or better. Higher rates of MMR were seen in patients who has previously achieved a CCyR with any prior therapy (69% vs 25%, p<0.01), stopped their last TKI for intolerance rather than resistance (70% vs 30%, p<0.01), and in those with a baseline BCR::ABL1 PCR at the initiation of asciminib of less than 10% (84% vs 17%, p<0.01). While no difference was seen in the rate of MMR between those harboring a T315I mutation or not (54% vs 55%, p=0.68), a history of a non-T315I-TKDM was associated with a lower rate of MMR (27% vs 62%, p=0.014). No significant differences were seen between those who had previously received ponatinib or not (48% vs 65%, p=0.450), although those with ponatinib resistance, rather than intolerance, had a tendency toward a lower rate of MMR (33% vs 65%, p=0.11). While asciminib was generally well tolerated, haematological toxicity of any grade was seen in 18 (33%) patients, with grade 3-4 in 10 (18%). The commonest non-haematological toxicities were fatigue, fluid retention, rash, nausea, insomnia, bone pain and deranged liver function tests. One patient had recurrence of a pleural effusion thought to be related to treatment. One patient suffered a myocardial infarction, and one a recurrence of a DVT whilst on treatment but causative relationships to the drug were unclear. Discussion - Asciminib is a well-tolerated therapy for CML in a previously heavily treated group with multiple comorbidities. Prior responses to therapy appear an important predictor of response to asciminib, with those resistant to the last TKI, and those never achieving a CCyR on any prior therapy showing a lower rate of MMR. While the presence of T315I mutations does not appear to significantly impact on the response to asciminib, the presence of non-T315I mutations is associated with a lower rate of MMR. Importantly the standard dosing regimen in patients with T315I mutations is fivefold higher but whether this explains the discrepant responses to T315I and non-T315I mutations requires further investigation.

Assessment of Aging-Related Function Variations of P-gp Transporter in Old-Elderly Chinese CHF Patients Based on Modeling and Simulation.

P-glycoprotein (P-gp) is one of the most intensely studied transporters owing to its broad tissue distribution and substrate specificity. Existing research suggests that the risk of systemic exposure to dabigatran etexilate (DABE) and digoxin, two P-gp probe substrates in vivo, has significantly increased in elderly patients. We applied a model-based quantitative pharmacological approach to assess aging-related P-gp changes in the Chinese old-elderly population. Population pharmacokinetic (PopPK) modeling was first performed using clinical pharmacokinetic data to explore the effect of age on the pharmacokinetic characteristics of dabigatran (DAB, the active principle of DABE) and digoxin in elderly Chinese patients. Corresponding physiologically based pharmacokinetic (PBPK) models were established to further explain the elevated systemic exposure to these two drugs. Eventually, standard dosing regimens of DABE and digoxin were assessed in Chinese old-elderly patients with chronic heart failure (CHF) with different stages of renal impairment. PopPK analysis suggested that age as a covariate had an additional effect on the apparent clearance of these two drugs after correcting for creatinine clearance. PBPK simulation results suggested that disease-specific pathophysiological changes could explain DAB exposure in the young elderly. In the elderly population, 17.1% of elevated DAB exposure remained unexplained, and 25.5% of the reduced P-gp function associated with aging was ultimately obtained using sensitivity analysis. This value was further validated using digoxin data obtained by PBPK modeling. The simulation results suggest that CHF patients with advanced age and moderate-to-severe renal impairment require heightened vigilance for elevated exposure risk during the use of DABE and digoxin. Aging might be a significant risk factor for elevated systemic exposure to DAB and digoxin by reducing P-gp-mediated efflux in the Chinese old elderly population.

Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives.

The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.

Personalized Lu177 Theranostic Dosimetry Using a Single Beta-Particle In Vivo Microdosimeter

<h3>Purpose/Objective(s)</h3> Achieving optimal tumor dose while minimizing organ at risk (OAR) uptake is a critical challenge for targeted radionuclide therapy (TRT), due to highly variable tumor uptake and biodistribution from patient to patient. Moreover, TRT is delivered using a standard dosing regimen for all patients, without knowledge if an ablative tumor dose, or critical OAR dose, has been reached. This potentially compromises outcomes that could be addressed by modulating the administered dose. SPECT-based dosimetry provides a snap-shot of body-wide dose distribution, but it is generally limited in availability and to a single time point. Therefore, methods for obtaining the total integrated dose for all patients are critically needed. A highly sensitive <i>in vivo</i> microdosimeter (IVµD) implanted within the tumor and OAR via biopsy needle solves this problem by monitoring the dose within the body in real time. Here, we demonstrate the world's first sub-mm³ single charged particle sensitive IVµD and its applicability to Lu¹⁷⁷-based TRT. The low power consumption (<0.6 mW) and miniaturized form factor (0.27 mm³) are compatible with <i>in vivo</i> implantation for continuous monitoring of TRT delivery and personalized dosing. <h3>Materials/Methods</h3> To achieve single particle detection, an array of ultra-small (1 µm²) diodes are integrated with in-pixel amplifiers on a 0.9 mm² integrated circuit. For each emitted beta-particle that intersects the chip, ∼1/3 of the deposited energy in the diode's depletion region creates electron-hole pairs. The generated electrons are then integrated on the diode's parasitic capacitor (C_p). Because the amplitude of the voltage signal, V_p, is inversely proportional to C_p, a nearly minimum size diode (1 µm², with C_p = 2.4 fF) maximizes V_p from the single hit. The diodes are arranged in a 64 ⨉ 64 array, providing a total detection area of 512 ⨉ 512 µm² in a monolithic silicon chip-let. Lu¹⁷⁷ is diluted to 10 different concentrations ranging from 1.5 ⨉ 10⁻³∼1.2 µCi/µL, equivalent to 0.18∼146 %ID/g assuming 800 µCi of injection, matching and exceeding the therapeutic dose range of 0.97∼649 Gy. The device is submerged in the tube and measures the activity of each solution for more than 40 minutes. <h3>Results</h3> The measured counts per minute (CPM) is highly proportional to the concentration over a wide range without saturation. The least square linear regression relationship between the measured CPM and concentration is CPM = 1290 ⨉ concentration (in µCi/µL), and highly linear with an R² value of 0.9998. The measured mean and the standard error of CPM ranges from 1.9 ± 0.8 CPM (at 1.5 ⨉ 10⁻³ µCi/µL, or 0.18 %ID/g) to 1510 ± 46 CPM (at 1.2 µCi/µL, or 146 %ID/g), demonstrating the wide dynamic range necessary to measure low uptake organs at risk and high uptake tumors. <h3>Conclusion</h3> A sub-mm³ diode based IVµD capable of detecting single beta-particles in real-time was demonstrated using solutions of Lu¹⁷⁷. We envision that such a device can be used to optimize TRT dosing on a per-patient level improving clinical outcomes.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Heparin-Peptide Nanogranules for Thrombosis-Actuated Anticoagulation.

Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported. Biophysical studies demonstrate this responsive behavior is due to the sequestration of heparin within self-assembling peptide nanofibrils and its mechanically actuated decoupling to elicit antithrombotic effects at the clotting site. In vivo studies show these unique properties converge to allow subcutaneous nanogranule depots to extend heparin serum concentrations for an order of magnitude longer than standard dosing regimens while enabling prolonged and controlled anticoagulant activity. This biohybrid delivery system demonstrates a potentially scalable platform for the development of safer, easier to administer, and more effective antithrombotic nanotechnologies.