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Renal safety pharmacology: value of sensitized experimental models
1Laboratoires Guerbet, Research Division, Roissy-Charles de Gaulle, France.
Abstract:
The kidneys are an important target for toxic effects of drug candidates. It is mandatory to select accurate, clinically relevant parameters in order to be in a position to detect putative nephrotoxic effects during the safety pharmacology programme. The glomerular filtration rate appears to be of major interest since it is associated with the definition of acute renal failure. Measurement of the renal blood flow, proteinuria, enzymuria, fractional excretion of sodium, etc. are also highly useful to detect any possible renal impact of a new compound. Although the rat is, by far, the most widely used animal species, there are no specific (clinically relevant) reasons to choose it. Various parameters may vary according to the species, sex, strain, age, etc. Since in most cases acute renal failure occurs following administration of drugs in patients with pre-existing risk factors, it is suggested that sensitized animal models be validated and used (salt depletion, dehydration, co-administration of pharmacologic agents, etc.).
Insights
Accurate safety pharmacology requires monitoring kidney function parameters like glomerular filtration rate to detect drug-induced nephrotoxicity. Validating sensitized animal models is crucial for predicting clinical renal risks.
Area of Science:
- Pharmacology
- Toxicology
- Nephrology
Background:
- Kidneys are a primary target for drug-induced toxicity.
- Detecting nephrotoxicity during safety pharmacology requires precise, clinically relevant parameters.
- Glomerular filtration rate is key for defining acute renal failure.
Purpose of the Study:
- To highlight essential parameters for detecting drug-induced nephrotoxicity.
- To discuss the limitations of current animal models in safety pharmacology.
- To advocate for the use of validated, sensitized animal models for better clinical prediction.
Main Methods:
- Review of established and potential biomarkers for renal function.
- Analysis of species-specific variations in physiological parameters.
- Consideration of pre-existing risk factors in patient populations.
Main Results:
- Glomerular filtration rate, renal blood flow, proteinuria, enzymuria, and fractional sodium excretion are vital parameters.
- Rat models, while common, lack specific clinical relevance for all studies.
- Parameter variability exists across species, sex, strain, and age.
Conclusions:
- Accurate detection of nephrotoxicity necessitates careful selection of clinically relevant parameters.
- Sensitized animal models, mimicking patient risk factors, should be validated and utilized.
- Standardized approaches are needed to improve the predictive value of preclinical safety pharmacology for renal effects.