A framework for joint modeling and joint assessment of efficacy and safety endpoints for probability of success evaluation and optimal dose selection

2011 ◽  
Vol 31 (5) ◽  
pp. 401-419 ◽  
Author(s):  
Weili He ◽  
Xiting Cao ◽  
Lu Xu
Keyword(s):  
Optimal Dose ◽  
Joint Modeling ◽  
Efficacy And Safety ◽  
Dose Selection ◽  
Probability Of Success ◽  
Success Evaluation ◽  
Joint Assessment

scholarly journals Pharmacogenetics in drug development

2005 ◽  
Vol 360 (1460) ◽  
pp. 1579-1588 ◽  
Author(s):  
Alun D McCarthy ◽  
James L Kennedy ◽  
Lefkos T Middleton
Keyword(s):  
Pharmaceutical Companies ◽  
Efficacy And Safety ◽  
Plasma Drug ◽  
Dose Selection ◽  
Drug Discovery And Development ◽  
Safety Issues ◽  
Drug Choice ◽  
Probability Of Success ◽  
Safety Studies ◽  
Appropriate Therapy

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx—the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success—the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.

scholarly journals Efficacy and Safety of Daratumumab Combined With All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma

2021 ◽  
Author(s):  
Kristine A. Frerichs ◽  
Monique Christina Minnema ◽  
Mark-David Levin ◽  
Annemiek Broijl ◽  
Gerard MJ Bos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stable Disease ◽  
Immune Cell ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Flow Cytometric Analysis ◽  
Optimal Dose ◽  
Efficacy And Safety ◽  
Cd38 Expression

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

scholarly journals Age-Related Changes in the Hepatic Pharmacology and Toxicology of Paracetamol

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Sarah J. Mitchell ◽  
Alice E. Kane ◽  
Sarah N. Hilmer
Keyword(s):  
Older Adults ◽  
Hepatic Clearance ◽  
Optimal Dose ◽  
Interindividual Variation ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Dose Selection ◽  
Age Related ◽  
Accidental Overdose ◽  
Toxicity Of Drugs ◽  
Age Related Changes

Optimal pharmacotherapy is determined when the pharmacokinetics and pharmacodynamics of the drug are understood. However, the age-related changes in pharmacokinetics and pharmacodynamics, as well as the increased interindividual variation mean optimal dose selection are a challenge for prescribing in older adults. Poor understanding of how hepatic clearance and toxicity are different with age results in suboptimal dose selection, poor efficacy, and/or increased toxicity. Of particular concern is the analgesic paracetamol which has been in use for more than 50 years and is consumed by a large proportion of older adults. Paracetamol is considered to be a relatively safe drug; however, caution must be taken because of its potential for toxicity. Paracetamol-induced liver injury from accidental overdose accounts for up to 55% of cases in older adults. Better understanding of how age affects the hepatic clearance and toxicity of drugs will contribute to evidence-based prescribing for older people, leading to fewer adverse drug reactions without loss of benefit.

scholarly journals Efficacy and safety of bevacizumab in the treatment of adult gliomas: a systematic review and meta-analysis

BMJ Open ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. e048975
Author(s):  
Huan Wang ◽  
Jianxin Guo ◽  
Tianze Wang ◽  
Kai Wang ◽  
Zhuojun Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Large Scale ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Secondary Outcome ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Significant Difference ◽  
Clinical Centre

ObjectiveTo assess the efficacy and safety of bevacizumab (BEV) in patients with glioma.DesignSystematic review and meta-analysis.ParticipantsAdults aged 18 years and above, whose histology was confirmed to be malignant glioma.Primary and secondary outcome measuresThe main indicators included progression-free survival (PFS) rate and overall survival (OS) rate, and the secondary indicators were adverse reactions.ResultsA total of 11 clinical centre trials were included in this study for meta-analysis, including 2392 patients. The results of the meta-analysis showed that the median PFS rate of the BEV group was significantly higher than that of the non-BEV group (p<0.00001). When comparing PFS between two groups, we found that the PFS in the BEV group was higher than that in the non-BEV group at 6 months (OR 3.31, 95% CI 2.74 to 4.00, p<0.00001), 12 months (OR 2.05, 95% CI 1.70 to 2.49, p<0.00001) and 18 months (OR 1.31, 95% CI 1.02 to 1.69, p=0.03). But at 24 months (OR 0.83, 95% CI 0.50 to 1.37, p=0.47), there was no significant difference between the two groups. At 30 months (OR 0.62, 95% CI 0.39 to 0.97, p=0.04), the PFS of the BEV group was lower than that of the non-BEV group. Moreover, The results showed that BEV had no significant effect on improving OS, but the adverse reaction in BEV group was significantly higher than that in non-BEV group.ConclusionThe evidence suggests that BEV can significantly prolong the PFS of patients with glioma within 18 months and shorten the PFS of patients after 30 months. This limitation may be related to the subgroup of patients, the change of recurrence mode, the optimal dose of drug, the increase of hypoxia, the enhancement of invasiveness and so on. Therefore, it is necessary to carry out more samples and higher quality large-scale research in the future.

scholarly journals Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1270
Author(s):  
Mònica Millán ◽  
Núria DeGregorio-Rocasolano ◽  
Natàlia Pérez de la Ossa ◽  
Sílvia Reverté ◽  
Joan Costa ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Optimal Dose ◽  
Iron Chelator ◽  
Good Clinical Outcome ◽  
Dose Selection ◽  
Iron Saturation ◽  
Deferoxamine Mesylate ◽  
The Impact ◽  
New Evidence

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients.

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