Safety studies pharmacodynamics

An additional consideration is the safety assessment of agents that will be used for challenge stimuli in the evaluation of pharmacodynamics. In some cases, there is a long history of uneventful clinical use of tests, for example, bronchial challenge with histamine and methacholine. If used in a similar manner, there may be no need to consider performing safety studies in... 

The animal species chosen for the later nonclinical safety studies should be responsive to the pharmacodynamic action(s). If the standard laboratory species are not responsive, the applicant should justify the choice of species selected or any supplementary tests if these are deemed appropriate. 

The preceding section describes the kinds of preclinical safety studies performed to enable the characterization of both the pharmacodynamics and the... 

For the purposes of simplicity, the description of each study is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety (and pharmacodynamic) parameters are also studied. 

While formulation interactions often are subject to in vitro investigations, the section below presents a particular example of an in vivo formulation interaction study (CPMP/EWP/QWP/1401/98 2002) a potential interaction of a drug in medical practice frequently given concomitantly with another drug (i.e. both mixed in a syringe) was subject to a clinical study which is illustrated below. For the purposes of simplicity, the description is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety and pharmacodynamic parameters were also studied. 

Amaravadi RK, Schilder RJ, Dy GK, et al (2011) Phase 1 study of the smac mimetic TL32711 in adult subjects with advanced solid tumors lymphoma to evaluate safety, pharmacokinetics, pharmacodynamics and anti-tumor activity. In 2011 annual AACR conference, Orlando, FL... 

This consists of information from the complete clinical data package selected for its relevance to the new region. Pharmacokinetic (PK), pharmacodynamic (PD) and early dose-response date should all be included. If a bridging clinical study between the foreign data and the new region s population is needed, this may be a pharmacokinetic study, or pharmacodynamic demonstration of efficiency or a full clinical efficacy and safety study, with perhaps one center running a pharmacokinetic study add-... 

Pinquier JL, CaplainH, Durrieu G, ZieleniukI, RosenzweigP. Safety and pharmacodynamic study of befloxatone after fluoxetine withdrawal. Clin Pharmacol Ther 99%) 63, 187. 

Three TLR9 agonists that induce distinct immune response profiles based on their structures have been selected for clinical studies. lMO-2055 is a lead clinical candidate for the treatment of cancers. The safety and pharmacodynamic activity of lMO-2055 have been studied in Phase-1 rising-dose trials in healthy and cancer subjects. A dose-dependent transient migration of lymphocytes from peripheral blood, activation of surface markers on immune cells, and elevation of plasma cytokines has been observed, consistent with immune-stimulatoiy activity of IMO-2055. No significant acute phase or proinflammatory activity, including no effects on cortisol, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were observed [41, 115-118]. 

Chan, M.Y. et al. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. Journal of Thrombosis and Haemostasis 6,789-796,2008. 

The overall objective of clinical trials is to establish a drug therapy that is safe and effective in humans, to the extent that the risk-benefit relationship is acceptable. The ICH process has developed an internationally accepted definition of a clinical trial as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. ... 

A summary of the results of the various pharmacological studies, with particular emphasis on results which may be relevant to the evaluation of the safety of residues of the substance. A.2.1 Pharmacodynamics A.2.2 Pharmacokinetics... 

A study of GSK1278863A (structure undisclosed) in healthy adult subjects for the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat oral doses up to 300 mg for 14 days has also been completed [69]. Finally, AKB-6548 (structure undisclosed) has completed Phase la clinical trials in 48 healthy volunteers for the potential treatment of anemia. Preliminary results claim that doses that significantly increase plasma EPO without raising VEGF levels were identified and that further clinical trials are planned [70]. 

As it is often very difficult to quantify therapeutic performance with pharmacodynamic and clinical studies, pharmacokinetic studies are usually the most suitable tool to describe the performance of the drug product in vivo. Once a relationship between the plasma concentration of the drug or active moiety and the therapeutic effect has been established, BA may be considered to be the perfect surrogate parameter for efficacy and/or safety of a drug product. 

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