During drug development, it is necessary to establish that the drug has No Observed Adverse Effects Level (NOAEL). The FDA sees this as a necessity for any New Drug Application (NDA). To establish the robustness and reproducibility of the data, GLP toxicology studies FDA guidelines have to be followed.
Good Lab Practices (GLP) are a set of instructions and management to ensure proper procedures and documentation are available. Establishing NOAEL allows a drug to pass from nonclinical testing to clinical testing.
While this is mandatory for NDAs, it is also required for extending the profile for existing drugs. This helps clear the profile for new indications relevant to the drug. Other changes like those in the formulation and route of administration are also included.
Tox study plays a central role in establishing NOAEL. A goal of the GLP toxicology studies FDA guidelines is to ensure the safety of the patient. The toxicology study ensures the safety of the formulation, administration, and effects of the drug.
Toxicokinetics and Drug Safety
TK assay are a part of the toxicology study and tests should be conducted as per FDA guidelines. These assays measure the systemic exposure of a body to a substance. The drug is followed through the processes of ADME (Absorption, Distribution, Metabolism, and Elimination). This allows following a relationship between dose and drug administration and its effects on animals over time.
As is evident, the TK assay is closely tied to relevant PK studies. Determining the repeat-dose PK profile of a drug provides excellent data for Toxicokinetics and its determination for tox study. As the study progresses, the toxicokinetic profile evaluates the potential of a substance to accumulate in organs or tissues.
In many cases, direct measurement of tissues may not be possible. Drug concentration in blood serum or plasma is used as an indicator in these cases. Though it is rare, more invasive methods could be used to collect samples where necessary.
Answering Tox Questions with Toxicokinetic Assay
To stay compliant with FDA guidelines, The TK assay should be able to quantify the fraction of the substance present in tissues, especially as related to systemic exposure. Several aspects need detailing, ranging from the absorption and relevant ADME parameters to the effects of the dose.
The toxicokinetic study at this point may choose to follow two protocols. The full protocol answers all relevant questions. Following a reduced protocol answers only the main questions. In cases where other parts of the study or previously existing data answer some questions, using the reduced protocol is viable.
The reduced protocol is the more common method used, in general. A full protocol requires greater in vivo testing and adds to the monetary and time investment in the study. It also has ethical considerations as more animals are required for the study. A reduced protocol answers only the main questions with the aim of corroborating toxicology findings and its interpretation.
FDA guidelines recommend that at least two mammalian species be a part of the tox study. One of these species has to be a non-rodent.