Repeat Dose Studies

Single dose toxicity studies establish the lethal dose and MTD in rodents and non-rodents, respectively. Based on findings of these studies, doses for the pilot (7 or 14-day) toxicity studies are chosen, after which the pivotal (28-day) studies are conducted. A pivotal study will generally have a control group, at least three dose groups and also sets of recovery groups. Animals of the recovery groups are maintained on-study after the last dose administration for the duration of the recovery period. Clinical observations, detailed physical observations, body weight and food consumption, ophthalmoscopy, electrocardiogram (for non-rodents only), hematology, coagulation, clinical chemistry and urinalysis parameters, gross changes (at necropsy) and histopathology evaluation are all integral parts of repeat dose toxicity studies. Plasma drug levels are estimated post dosing, generally after the first and last doses and sometimes also midway through the study. Any special tests or parameters specific to the class of test drugs may also be included in such studies.

Data obtained from the animals of the main study groups will establish the effect of repeated dosing on the various organs and tissues. The recovery group data will help in understanding if the effects caused by the test drug administration are of a transient nature and are reversed when dosing is stopped or if the damage is of a more permanent nature. Evaluation of the available data will help in determining the No Observed Effect Level (NOEL) and /or No Observed Adverse Effect Level (NOAEL). These are two important numbers, which along with plasma exposure data are used to arrive at the first dose that will be administered to humans (First Human Dose (FHD)).

Safety Pharmacology Studies

Safety pharmacology studies are designed to establish if the test drug has any effect on the functioning of the three major systems – respiratory, neurological and cardiovascular. The respiratory and neurological studies are conducted in male rats, while the cardiovascular studies are conducted in the non-rodent species. Effect of the test drug is evaluated on appropriate parameters, at predetermined time points after dose administration.

Respiratory function is evaluated in conscious rats, using either whole body or head-out plethysmography (an instrument for measuring changes in volume). Information on the air displaced by the animal’s breathing is collected, integrated and collated to arrive at the effect or lack thereof on the various parameters of respiratory function.

The effect of the test drug on the functioning of the central and peripheral nervous systems is assessed using a battery of tests which are collectively called the Functional Observation Battery or FOB. Effect on motor activity is also evaluated.

Cardiovascular evaluation can be conducted in either anesthetized or freely moving, conscious animals. The latter method is preferred because the data obtained is not complicated or compromised by the effect of the anaesthetic. Transmitters are surgically implanted in the animals so that the electrocardiogram (ECG) signals can be continuously transmitted to the receivers mounted on the cages and then on to remote data acquisition systems.

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