Efficacy Of Different Dosing Regimens Research Articles

Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

A phase I study of highly potent oral ATR inhibitor (ATRi) tuvusertib plus oral PARP inhibitor (PARPi) niraparib in patients with solid tumors.

3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase and poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib and niraparib may synergistically enhance synthetic lethality and increase apoptosis. Part B1 of the DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: Part B1 of this open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable solid tumors refractory to standard treatment. The primary objective was to determine safety (including maximum tolerable dose and recommended dose(s) for expansion [RDE]). Secondary and tertiary objectives included determination of the pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of different dosing regimens of tuvusertib plus niraparib. Multiple continuous and intermittent schedules were explored with tuvusertib doses ranging from 90–180 mg once-daily (QD) and niraparib doses from 100–200 mg QD. A partial ordering continual reassessment method was used to identify the RDEs. Results: As of 02 January 2024, 43 patients had been enrolled (all with baseline body weight <77kg or platelet count <150,000/mm3); 13 patients remained on treatment. Ten (26.3%) patients had dose-limiting toxicities (DLTs). The most common DLT was grade 3 anemia requiring blood transfusion (n=4; 10.5%); the most frequent grade ≥3 treatment-emergent adverse events were anemia (n=18; 41.9%), platelet count decrease (n=6; 14.0%) and fatigue (n=4; 9.3%). The PK of tuvusertib when combined with niraparib was consistent with that of tuvusertib monotherapy, suggesting a lack of any clinically meaningful mutual drug–drug interactions. Dose-dependent ɣ-H2AX inhibition (proximal PD marker) was observed at tuvusertib doses ≥130 mg QD. Preliminary efficacy data show 5 (15.6%) responses (3 confirmed) by RECIST v1.1 in 32 evaluable patients: 2 in patients with epithelial ovarian cancer (EOC; 1 with BRCA1-mutant [ BRCA1m] PARPi-resistant EOC, 1 with BRCA-wild type homologous recombination deficiency-positive EOC) and 1 each in patients with non-small cell lung cancer, estrogen receptor-positive HER2-negative BRCA1m breast cancer, and BRCA1m PARPi-resistant pancreatic cancer. Tuvusertib 180 mg QD and niraparib 100 mg QD or tuvusertib 90 mg QD and niraparib 200 mg QD, both given in a 1 week on/1 week off schedule, were identified as RDEs. Conclusions: The combination of tuvusertib plus niraparib, each administered on a 1 week on/1 week off schedule, has a manageable safety profile and is suitable for further investigation. A combination study in patients with PARPi-resistant EOC is planned. Clinical trial information: NCT04170153 .

Comment on Manzoor, H. et al. Efficacy of Different Dosing Regimens of IgE Targeted Biologic Omalizumab for Chronic Spontaneous Urticaria in Adult and Pediatric Populations: A Meta-Analysis. Healthcare 2022, 10, 2579.

In December 2022, the paper "Efficacy of Different Dosing Regimens of IgE Targeted Biologic Omalizumab for Chronic Spontaneous Urticaria in Adult and Pediatric Populations: A Meta-Analysis" was published in the Healthcare journal [...].

Evaluation of the Efficacy of Optimized Two-Step-Administration Therapy with Ceftazidime/Avibactam for Treating Extensively Drug-Resistant Pseudomonas aeruginosa Pulmonary Infections: a Pharmacokinetic/Pharmacodynamic Analysis.

The objective of this pharmacokinetic (PK)/pharmacodynamic (PD) analysis was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) for the treatment of pulmonary infections by extensively drug-resistant (XDR) Pseudomonas aeruginosa using optimized two-step administration therapy (OTAT) and traditional infusion (TI). We used Monte Carlo simulations (MCS) to integrate PK parameters with PD parameters to assess the adequacy of CZA dosing in critically ill patients with XDR P. aeruginosa pulmonary infections. Dosing models were as follows: 2.5 g q8h, 2.5 g q6h, 4 g q8h, 4 g q6h, 1.25 g q8h, 1.25 g q6h, and 0.94 g q12h. MCS showed that the cumulative fraction of response of all dosing regimens of OTAT was higher than 90%. The probability of target attainment of all dosing regimens of OTAT at MICs (minimal inhibitory concentrations) between 16 mg/L and 32 mg/L was higher than that of TI. Based on these models, PK/PD goals were met with OTAT regimens, even with high MICs (>16 mg/L) compared to traditional infusion (TI) intervals. Thus, this study indicates that OTAT with sufficient PK exposure could improve the efficacy of CZA in critically ill patients with XDR P. aeruginosa pulmonary infections.

Efficacy of Different Dosing Regimens of IgE Targeted Biologic Omalizumab for Chronic Spontaneous Urticaria in Adult and Pediatric Populations: A Meta-Analysis.

Chronic urticaria is a debilitating skin condition that is defined as itchy hives at least twice a week and lasting for six or more weeks, with or without angioedema. Chronic spontaneous urticaria (CSU) is a form of disease that is witnessed in two-thirds of those with chronic urticaria. This meta-analysis explores the efficacy of differential dosages of omalizumab for outcomes of weekly itching scores, weekly wheal scores, urticarial assessment score 7 (UAS7), and responder rates. Adhering to PRISMA Statement 2020 guidelines, a systematic search of PubMed/MEDLINE, Scopus, Embase, and Web of Science was conducted until 15 September 2022. A combination of the following keywords was used: omalizumab and chronic urticaria. Data comprising clinical trial ID, name, author/year, country, dosage and time of intervention, inclusion criteria, mean age, female gender, and racial grouping information were obtained. The meta-analytical outcomes were analyzed in RevMan 5.4. The risk-of-bias assessment was conducted using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). A total of 10 trials comprising 1705 patients with CSU were included. Notably, 1162 belonged to the intervention group, while 543 were controls. A total of 70.4% of the participants were female in the intervention group, while 65.6% of them were female in the control group. The overall mean age was 38.64 ± 10.66 years. Weekly itch score outcomes were most notable with 150 mg dosage (Cohen's d = -2.6, 95% CI = -4.75, -0.46, p = 0.02). The weekly wheal score outcomes had the largest effect size with 300 mg dosage (Cohen's d = -1.45, 95% CI = -2.2, -0.69, p = 0.0002). For UAS7 outcomes, the largest effect size was yielded with 150 mg dosage (Cohen's d = -6.92, 95% CI: -10.38, -3.47, p < 0.0001). The response rate to omalizumab had a likelihood of being higher with 300 mg of intervention compared to placebo (OR = 8.65, 95% CI = 4.42, 16.93, p < 0.0001). Well-rounded urticarial symptom resolution was observed with 150 mg and 300 mg dosages of omalizumab. Improvement of UAS7 was more comparable with 150 mg dosage, whereas the chance of response to treatment was higher with 300 mg dosage. Our findings support omalizumab as an effective intervention for adult and pediatric populations that are resistant to many therapies, including high-dose H1-antihistamines.

POS-452 SAFETY AND EFFICACY OF ANG-3070 IN PATIENTS WITH PRIMARY PROTEINURIC KIDNEY DISEASE: A PHASE 2 STUDY DESIGN

Primary proteinuric kidney diseases (PPKDs) are among the leading causes of end-stage kidney disease (ESKD). Receptor tyrosine kinases, including platelet-derived growth factor receptor and discoidin domain receptors 1 and 2, are thought to play a role in the progression of PPKDs to ESKD. ANG-3070, a selective oral tyrosine kinase inhibitor, has demonstrated beneficial effects in chronic kidney disease animal models. Here we describe the design of a proof-of-concept study of ANG-3070 in the treatment of patients with PPKD who have persistent proteinuria while on standard of care (SOC). Planned enrollment is 100 patients for this 12-week, randomized, double-blind, placebo-controlled study. Eligible patients have biopsy-proven PPKD and persistent proteinuria (≥1 g/day) while on SOC, which may include maximum tolerated RAAS inhibitors. Patients will be randomized 1:1:1:1 to ANG-3070 200 mg or 400 mg once daily, or 300 mg twice daily, or placebo (Figure). The primary endpoint is the percentage change in 24-hr urinary protein at Week 12 compared to baseline. Key secondary endpoints evaluated at Week 12 include percentage change in 24-hr urinary albumin, number of patients with complete remission in proteinuria (24-hr urinary protein <300 mg), number of patients with partial remissions in proteinuria (24-hr urinary protein reduction of ≥50% from baseline and a 24-hr urinary protein <3.5 g if baseline 24-hr urinary protein >3.5 g), number of patients with ≥50% reduction in 24-hr urinary protein from baseline, and number of patients with ≥50% reduction in 24-hr urinary albumin from baseline. An independent data monitoring committee will review safety throughout the study. Enrollment will begin in 2021. This phase 2 study will provide data about the safety and efficacy of different dosing regimens of ANG-3070 in PPKD patients that will inform the design of a phase 3 study.

Pharmacokinetic/pharmacodynamic modelling to evaluate the efficacy of various dosing regimens of ceftazidime/avibactam in patients with pneumonia caused by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae: a multicentre study in northern China

The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections. A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS. The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5×MIC) target were as follows: for patients with creatinine clearance (CLCr) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CLCr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h. This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia.

An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens.

The pharmaceutical industry has invested significantly in antibody-drug conjugates (ADCs) with five FDA-approved therapies and several more showing promise in late-stage clinical trials. The FDA-approved therapeutic Kadcyla (ado-trastuzumab emtansine or T-DM1) can extend the survival of patients with tumors overexpressing HER2. However, tumor histology shows that most T-DM1 localizes perivascularly, but coadministration with its unconjugated form (trastuzumab) improves penetration of the ADC into the tumor and subsequent treatment efficacy. ADC dosing schedule, e.g., dose fractionation, has also been shown to improve tolerability. However, it is still not clear how coadministration with carrier doses impacts efficacy in terms of receptor expression, dosing regimens, and payload potency. Here, we develop a hybrid agent-based model (ABM) to capture ADC and/or antibody delivery and to predict tumor killing and growth kinetics. The results indicate that a carrier dose improves efficacy when the increased number of cells targeted by the ADC outweighs the reduced fractional killing of the targeted cells. The threshold number of payloads per cell required for killing plays a pivotal role in defining this cutoff. Likewise, fractionated dosing lowers ADC efficacy due to lower tissue penetration from a reduced maximum plasma concentration. It is only beneficial when an increase in tolerability from fractionation allows a higher ADC/payload dose that more than compensates for the loss in efficacy from fractionation. Overall, the multiscale model enables detailed depictions of heterogeneous ADC delivery, cancer cell death, and tumor growth to show how carrier dosing impacts efficacy to design the most efficacious regimen.

Effective Dosage of Oral Vancomycin in Treatment for Initial Episode of Clostridioides difficile Infection: A Systematic Review and Meta-Analysis.

Background: Oral vancomycin is a first line treatment for an initial episode of Clostridioides difficile infection. However, the comparative efficacy of different dosing regimens is lacking evidence in the current literature. Methods: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. from inception to May 2019. Only articles published in English are reviewed. This meta-analysis compares the effects of low dose oral vancomycin (<2 g per day) versus high dose vancomycin (2 g per day) for treatment of initial Clostridioides difficile infection. Results: One randomized controlled trial and two retrospective cohort studies are included. A total of 137 patients are identified, 53 of which were treated with low dose oral vancomycin (39%) and 84 with high dose oral vancomycin (61%). There is no significant reduction in recurrence rates with high dose vancomycin compared to low dose vancomycin for treating initial episodes of non-fulminant Clostridioides difficile infection ((odds ratio (OR) 2.058, 95%, confidence interval (CI): 0.653 to 6.489). Conclusions: Based on limited data in the literature, low dose vancomycin is no different than high dose vancomycin for treatment of an initial episode of Clostridioides difficile infection in terms of recurrence rate. Additional large clinical trials comparing the different dosages of vancomycin in initial Clostridioides difficile infection are warranted.

Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens.

This meta-analysis examined the efficacy of different dosing regimens containing rituximab (RTX) in treating pemphigus. The analysis included 578 patients with pemphigus from 30 studies. Seventy-six percent of patients achieved complete remission (CR) after 1 cycle of RTX. Mean time to remission was 5.8 months, with a remission duration of 14.5 months and a 40% relapse rate. Eighteen patients (3.3%) developed serious adverse effects. The pooled estimate showed no significant differences in CR and relapse rates between patients treated with high-dose (near or ≥ 2,000 mg/cycle) vs. low-dose (< 1,500 mg/cycle) RTX. In the fully adjusted analysis, high-dose RTX was associated with longer duration of CR compared with low-dose RTX. No superiority of lymphoma protocol over rheumatoid arthritis or high-dose RTX over low-dose RTX was shown in other outcomes. RTX treatment is efficacious and well-tolerated in treating pemphigus. High-dose RTX treatment may lead to longer duration of remission. However, the choice of optimal regimen depends on the overall condition of the individual patient.

Alpha-1 proteinase inhibitor (a1PI) for preventing chronic lung disease in preterm infants.

Inflammation of the pulmonary parenchyma is one of the important mechanisms implicated in development of chronic lung disease (CLD) in preterm neonates. Release of enzymes and other anti - oxidants following cell damage is considered to be responsible for the damage to lung tissue. Various strategies have been attempted to counteract enzymatic damage to pulmonary parenchyma and to prevent CLD. This review examines the effectiveness of alpha 1 proteinase inhibitor (a1PI) for the prevention of CLD defined as requirement of supplemental oxygen at 36 weeks post menstrual age (PMA) in preterm neonates. A literature search was performed using the following databases: MEDLINE (1966 - February 2001), EMBASE (1980 -February 2001), CINAHL (1982 - February 2001), Cochrane Controlled Trials Register (Issue 1, 2001 of Cochrane Library) and abstracts from the annual meetings of the Society of Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991-2000). No language restrictions were applied. Selection criteria applied to the clinical trials were: 1. The population had to be preterm neonates 2. The intervention had to be administration of a1PI compared to placebo or no treatment within the first week of life 3. The eligible studies had to include any of the following outcomes: a. prevention of CLD b. reduction in duration of assisted ventilation c. reduction in the duration of oxygen requirement d. reduction in the need for systemic antiinflammatory therapy e. reduction in mortality or f. reduction in long term adverse neurological sequelae. 4. The trial had to be randomized or quasi-randomized. The methodological quality of the trials was assessed using the information provided in the studies and by personal communication with the authors. Data on relevant outcomes were extracted and the effect size was estimated and reported as pooled relative risk (RR), risk difference (RD) and weighted mean difference (WMD) as appropriate. Two strategies were used for analysis : 1. Comparison of 60 mg/kg/dose of a1PI administered for 4 days in first 2 weeks after birth, versus placebo and 2. Comparison of any dose of a1PI administered in first 2 weeks after birth, versus placebo. Two eligible studies were identified. The methodological qualities of identified studies were good. One study randomized infants to either placebo, or a1PI 60 mg/kg/dose for four doses while in the second study the same investigators explored the efficacy of different dose regimens of a1PI compared to placebo. There was no statistically significant difference in the development of CLD at 36 weeks PMA amongst all randomized infants. For 60 mg/kg/dose for four doses of a1PI compared to placebo the pooled RR was 0.64 [95% CI 0.35, 1.18] and RD was -0.10 [95% CI -0.23, 0.03] while for any doses of a1PI the pooled RR was 0.79 [95% CI 0.44, 1.41], RD was -0.05 [95% CI -0.17, 0.06]. There was a trend towards reduced risk of development of oxygen dependency at 28 days postnatal age, pooled RR 0.81 [95% CI 0.64, 1.01], RD -0.14 [95% CI -0.29, 0.00] for 60 mg/kg/dose for four doses of a1PI compared to placebo. The pooled RR was statistically significant, RR 0.80 [95% CI 0.65, 0.98], RD -0.15 (95 % CI -0.29, -0.01) when any doses of a1PI were combined. The number of patients needed to treat (NNT) with a1PI to prevent one infant developing oxygen dependency at 28 weeks was 7. The benefits of short-term outcomes did not remain for long-term outcomes such as CLD and/or death at 36 weeks post menstrual age (pooled RR 0.84 [95% CI 0.53, 1.34], RD -0.06 [95% CI -0.20, 0.09] for 60 mg/kg/dose and pooled RR 0.95 [95% CI 0.61, 1.49], RD -0.02 [95% CI -0.15, 0.12] for any dose) or risk of development of long term neurodevelopmental abnormalities (pooled RR 1.29 [95% CI 0.43, 3.90], RD 0.03 [95% CI -0.11, 0.18]). In addition, no statistically significant difference was noted in other respiratory parameters such as duration of oxygen requirement or respiratory support. Prophylactic administration of a1PI did not reduce the risk of CLD at 36 weeks or long term adverse developmental outcomes in preterm neonates.

Clinical dose-regimen studies with latanoprost, a new ocular hypotensive PGF 2α analogue

This review summarizes recent short-term clinical studies evaluating the ocular hypotensive efficacy of different dose-regimens of latanoprost. When tested in ocular hypertensive and glaucoma patients concomitantly treated with timolol, 0.006% latanoprost given only in the evening, was found to be more effective than the same concentration given in the morning and evening. In patients with open angle, pseudoexfoliation and normal tension glaucoma not receiving other treatment, once-daily 0.005% latanoprost monotherapy was more effective than twice-daily 0.0015% latanoprost treatment. No significant differences were found in conjunctival hyperemia, sensory irritation or blood-aqueous barrier permeability between these two treatment regimens. Although the ocular hypotensive efficacy of once-daily application of the lower concentration (0.0015%) latanoprost was not investigated, we would conclude, based on the studies reviewed here, that at a concentration of 0.005%, once-a-day dosing of latanoprost is highly effective in significantly reducing intraocular pressure, causing only minimal, clinically acceptable short-term ocular side effects.

Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: The importance of iron availability in optimizing response

purpose: The goal of this study was to develop a short-term, practical, yet effective regimen for the perioperative use of recombinant human erythropoietin (r-HuEPO) as an alternative to autologous blood donation and/or homologous transfusion. In addition, changes in iron kinetics during accelerated erythropoiesis were examined. patients and methods: A randomized trial was performed on 24 healthy, iron-replete men. Subjects were given r-HuEPO in one of three dosage schedules, receiving a total dose of 1200 U/kg r-HuEPO subcutaneously: Group I—300 U/kg on Days 1, 4, 7, and 10; Group II—400 U/kg on Days 1,5, and 9; Group III—600 U/kg on Days 1 and 10. All subjects received 300 mg of elemental iron orally each day for 10 days beginning on Day 1. Complete blood counts (CBC), absolute reticulocyte counts, serum ferritin, serum iron, serum total iron-binding capacity (TIBC), and serum transferrin receptor protein concentrations were measured periodically during the 24-day study period. results: All groups showed a statistically significant increase in hematocrit, hemoglobin, and absolute reticulocyte count. There was no significant difference in response among the three groups with respect to hemoglobin and hematocrit. The mean maximum increases in hematocrit were 5.4 ± 1.7, 6.0 ± 2.1, and 7.2 ± 2.6 in groups I, II, and III, respectively. The increase in hematocrit positively correlated with log baseline ferritin (r = 0.682, p < 0.001). Administration of r-HuEPO was associated with a highly significant (p ≤ 0.0005) 74% decrease in serum ferritin, as well as a marked decrease in percent saturation of TIBC from 39% ± 14% to 14% ± 4% (p ≤ 0.0005). This was despite the fact that subjects lost less than 250 mL of blood as a result of venipunctures during the entire course of the study. conclusion: Each of these r-HuEPO dose schedules provides an effective, convenient regimen for perisurgical use. However, “normal” iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute r-HuEPO administration, even with oral iron supplementation. Nonetheless, these findings provide support for further study of the use of r-HuEPO as an alternative to autologous blood donation in the perisurgical setting.