Organ system studies renal

Several animal studies were located using the oral route for intermediate-duration and based on a combination of these studies, adverse effects have been reported in many organ systems. Hepatic, renal, and hematologic (Bombard et al. 1988 Carlson 1977 Hollingsworth et al. 1956 NTP 1987) effects have been the most consistent observations. The MRL was based on a minimal LOAEL of 188 mg/kg/day based on increased liver weights in rats. Since kidney effects involve hyaline droplet nephropathy, the renal effects were not considered to be a suitable basis for the MRL. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

In long-term therapy, perform periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies. 

Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of all new drugs are generally first performed in normal animals. Where appropriate, studies on disease models are performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see whether blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy after oral and parenteral administration. 

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