Toxicokinetics dosing regimens

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

Once a compound is selected for development, further studies are performed in animals and man to support the safety assessment and ensure that optimum dosing regimens are selected. Definitive in vivo PK and toxicokinetic studies are performed but also more detailed in vitro studies, particularly for the assessment of drug-drug interactions. ADME/PK support is continued throughout development (pre-clinical and phases I-IV) and a summary list of the main activities is shown in Table 4. 

Detailed drug metabolism and disposition studies in animals were considered of less value since the biosynthetic product was identical to the natural human protein and would be expected to undergo identical absorption, metabolism, and excretion. Toxicokinetics were also considered to be less valuable than those performed with most new xenobiotics, but were used to support the higher daily dosing regimens used in the toxicology studies. 

Kinetic studies are important for the safety evaluation of interferons and interleukins. Both pharmaco- and toxicokinetics have been evaluated in single- and, in some cases, multiple-dose studies. Use of pharmacodynamic endpoints or serum markers of biological response are especially important in those cases where the serum levels are lower than the limits of detection of the assay for the test material. In addition, studies to investigate the accumulation of (modified) products with long half-lives in relation to the dosing regimen are useful. Tissue distribution studies have not been components of the safety evaluation of interferons and interleukins. 

For consideration of the selection of animal species for repeated dose studies see section 3.3. The route and dosing regimen (e.g., daily versus intermittent dosing) should reflect the intended clinical use or exposure. When feasible, these studies should include toxicokinetics. 

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