Inflammation is a process by which white blood cells and substances they release to protect the body from infection with foreign organisms, such as viruses and bacteria. There’re more than 20 anti-inflammatory drugs available commercially, which are used worldwide for analgesic, antipyretic effects in patients with different medical conditions. Pharmacodynamics (PD) helps explain the relationship between the dosage and response (drug's effects). Notably, Creative Biolabs is committed to anti-inflammatory drug discovery and skilled at assessing multiple pharmacological parameters to lower risks through drug development. Our clinical PD services include study design, high-quality trial execution, data capture and analyses, and strictly comply with international regulatory standards.
The nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively chosen for their analgesic and anti-inflammatory efficacy. The half-live of NSAIDs vary but in general can be classified into "short-acting" (less than 6 hours, including ibuprofen, ketoprofen, indomethacin, and diclofenac) and "long-acting" (more than 6 hours, including celecoxib, naproxen, meloxicam, piroxicam, and nabumetone). A number of NSAIDs, for instance, aspirin, ibuprofen, and indomethacin, are also exploited for the initial treatment of dysmenorrhea and fever of unknown origin. These agents usually do not change the course of disease processes, where they work for symptomatic relief. Moreover, aspirin, ibuprofen, and naproxen are over-the-counter (OTE) drugs in most countries. And the number of NSAID users is still growing because of the widespread use of acetylated salicylates (aspirin) for the prevention of thromboembolic complications of cardiological and neurological conditions.
NSAIDs differ in their dose, drug interactions, and side effects, most of which are absorbed completely, show negligible first-pass hepatic metabolism, bond tightly to serum proteins, and have small volumes of distribution. Inhibition of kidney prostaglandin synthesis by NSAIDs causing a decline in kidney blood flow and tubular secretion of drugs appears to be a key mechanism for loss of blood pressure control with some anti-hypertensive drugs, such as P-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. There may be evidence that this type of interaction is least likely for aspirin, ibuprofen, sulindac, and piroxicam. By contrast, these influences are most pronounced with naproxen and indomethacin.
In selective cases, only a few reports lost blood pressure control in patients receiving NSAIDs with calcium antagonists or central agonists. However, a mixed PD / pharmacokinetics (PK) interaction occurred in patients receiving calcium antagonists, indomethacin and felodipine, with a resulting increase in systolic blood pressure in non-hypertensive male groups. And from other PD studies, a synergistic effect of aspirin (<325 mg/day) and verapamil was found on thrombocytes. The bleeding tendency elevated due to enhanced effects of these agents on thrombocyte aggregation. As little as 1 g of aspirin has an ability to increase the bleeding time by ~60%.
Tab.1 Pharmacodynamics of nonsteroidal anti-inflammatory drugs (NSAIDs): qualitative aspects. (Lees, 2004)
PD aims to study the relationship between drug concentration at the site of action and biochemical, physiological effect. The response of receptors may be affected by the role of drugs competing for the same receptor, the functional state of the receptor or pathophysiological factors. Creative Biolabs has professional clinical team and modeling team particularly adept at PD assessments in many different therapeutic fields. We can provide the following services but not limited to listed ones.
Fig.1 Systems pharmacology PKPD modeling. (Danhof, 2016)
As required by clients, we can provide high-efficacy solutions and detailed test steps for anti-inflammatory disease drug, including study design, PD / PK input to pre-clinical and clinical development, in vitro evaluation (e.g. animal toxicology, safety and PD / PK data), non-compartmental and compartmental analysis, PD / PK modeling and simulation (e.g. population approach and disease-based modeling), and statistical analysis and reporting of PD / PK outcomes.
In drug discovery, in vitro models using tissue or organ baths describe the efficacy at a defined target and the selectivity of a molecule. And we can provide mature biological models that are independent of the systemic influence on in vivo preparations.
We’re able to conduct clinical PD testing for anti-inflammatory drugs and provide miscellaneous models for other diseases, such as cardiovascular, gastrointestinal, dermatological, hematology, metabolic, urological, and immune syndromes.
Correlations between administered dose and safety signals are key for assessment. After a model established, different dosage regimens can be simulated to predict exposure and save time and resources.
By integrating PD models with pre-clinical data, we can offer probabilistic risk analysis to eliminate candidates with a high risk of failure and facilitate anti-inflammatory drug developments more efficient in clinical trials.
All kinds of data analysis can be studied, such as PK, drug-drug interaction (DDI), single ascending dose (SAD), multiple ascending dose (MAD), thorough QT (TQT), food effect, hepatic impaired, renal impaired, site of absorption, radio-labeled mass balance, etc.
In addition to storage and security, we’re specialized in data collection, processing, and interrogation at the beginning of a study so that to maximize the utility of a dataset after it is locked.
As the first-class service provider in drug development, Creative Biolabs has won a high reputation for successfully accomplishing lots of challenging pharmacy projects and many pharmacological and PD assessments. Here, we’d like to provide a package service involving study design, PD analysis and consultation, interpretation of final results to lower time cycle and avoid predictable risks for anti-inflammatory drugs. Furthermore, our specialists are dedicated to supporting data analysis and reporting of results through final approval and during regulatory scrutiny, enabling clients to address questions of inflammatory reactions by high-efficacy drug candidates.
References
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